Georges Grau

Clinical Presentation, Haematological Indices and Management of Children with Severe and Uncomplicated Malaria in Douala, Cameroon

Publisher: Science Alert

Date: 10-2008

DOI: 10.3923/PJBS.2008.2401.2406

Abstract: This study carried out from January to June 2007, was undertaken to describe the clinical presentation of childhood malaria in Douala, a meso-endemic area as far as malaria transmission is concerned. One hundred and seventy eight children were enrolled after informed consent of their parents. The s le characteristics were recorded and clinical as well as preliminary laboratory investigations were performed. Thirty eight children coming for vaccination and counselling was targeted to serve as control. According to the results obtained, cerebral malaria (CM) seems to be associated with young age, whilst Malaria anaemia (MA) was predominant among older children. Hyperpyrexia and hyperparasitaemia were high among CM patients and 11.1% of them died, however, no neurological squeal was noticed immediately after discharge on those who survived. Haemoglobin and glycaemia were low on MA and CM patients these groups had low percentage in bed nets utilization as well. These results suggest that the clinical presentation of the disease differ with the geographic location and malaria disease features varies according to the severity. Such studies could contribute to the management of the disease.

Interleukin 6 production in experimental cerebral malaria: modulation by anticytokine antibodies and possible role in hypergammaglobulinemia.

Publisher: Rockefeller University Press

Date: 11-1990

DOI: 10.1084/JEM.172.5.1505

Abstract: The production of Interleukin 6 (IL-6) was studied during experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. IL-6 is present in the serum of mice with ECM, the highest concentrations being observed in mice with full-blown neurological syndrome. High IL-6 levels were also observed, however, in the absence of pathology in nonlethal malaria infection. These data suggest that IL-6 is produced in large amounts during malaria infection, but does not play a major role in the pathogenesis of ECM. A modulation of IL-6 production in ECM was achieved by in vivo treatment with other anticytokine antibodies: antibodies to interferon (IFN-gamma) or to tumor necrosis factor (TNF) abolished the rise of IL-6, while anti-IL-3 and anti-granulocyte/macrophage colony-stimulating factor antibodies only partially prevented this rise, suggesting that the two cytokines IFN-gamma and TNF are important intermediates in IL-6 production. Passive immunization against IL-6 did not prevent ECM, but significantly reduced serum IgG levels in malaria-infected mice. Thus, by its effects on B cells, IL-6 may be involved in hypergammaglobulinemia and immune-complex diseases, e.g., glomerulonephritis observed during malaria infection.

Complexity of immunological processes in the pathogenesis of malaria

Publisher: Springer Science and Business Media LLC

Date: 05-2006

DOI: 10.1038/NRI1858-C2

Pho4 Is Essential for Dissemination of Cryptococcus neoformans to the Host Brain by Promoting Phosphate Uptake and Growth at Alkaline pH

Publisher: American Society for Microbiology

Date: 22-02-2017

DOI: 10.1128/MSPHERE.00381-16

Abstract: Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, C. neoformans must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical level. Induction of phosphate acquisition genes leads to the uptake of free phosphate via transporters. By blocking the PHO pathway using a Pho4 transcription factor mutant ( pho4Δ mutant), we demonstrate the importance of the pathway for cryptococcal dissemination and the establishment of brain infection in murine models. Specifically, we show that reduced dissemination of the pho4Δ mutant to the brain is due to an alkaline pH tolerance defect, as alkaline pH mimics the conditions of phosphate deprivation. The end result is inhibited proliferation in host tissues, particularly in blood.

The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b

Publisher: Elsevier BV

Date: 2016

DOI: 10.1038/MTNA.2016.62

Immune mechanisms in bacterial and parasitic diseases: protective immunity versus pathology

Publisher: Elsevier BV

Date: 08-1991

DOI: 10.1016/0952-7915(91)90007-N

Abstract: The immunological mechanisms that contribute to resistance versus susceptibility to bacterial and parasitic infection are central to the development of improved prophylactic and therapeutic strategies. The delineation of two subsets of CD4+ T cells in the mouse that regulate these responses has provided a tremendous advance in understanding disease pathogenesis. The elucidation of protective immune mechanisms distinct from those that cause tissue damage should lead to the development of appropriate vaccines against these devastating illnesses.

TNF in vascular pathology: the importance of platelet-endothelium interactions

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/S0923-2494(93)80080-I

Dietary protein increases T-cell-independent sIgA production through changes in gut microbiota-derived extracellular vesicles

Publisher: Springer Science and Business Media LLC

Date: 27-07-2022

DOI: 10.1038/S41467-022-31761-Y

Abstract: Secretory IgA is a key mucosal component ensuring host-microbiota mutualism. Here we use nutritional geometry modelling in mice fed 10 different macronutrient-defined, isocaloric diets, and identify dietary protein as the major driver of secretory IgA production. Protein-driven secretory IgA induction is not mediated by T-cell-dependent pathways or changes in gut microbiota composition. Instead, the microbiota of high protein fed mice produces significantly higher quantities of extracellular vesicles, compared to those of mice fed high-carbohydrate or high-fat diets. These extracellular vesicles activate Toll-like receptor 4 to increase the epithelial expression of IgA-inducing cytokine, APRIL, B cell chemokine, CCL28, and the IgA transporter, PIGR. We show that succinate, produced in high concentrations by microbiota of high protein fed animals, increases generation of reactive oxygen species by bacteria, which in turn promotes extracellular vesicles production. Here we establish a link between dietary macronutrient composition, gut microbial extracellular vesicles release and host secretory IgA response.

LMP-420, un nouvelle approche thérapeutique pour le paludisme cérébral ?

Publisher: EDP Sciences

Date: 04-2006

DOI: 10.1051/MEDSCI/2006224343

Microparticles as Immune Regulators in Infectious Disease ? An Opinion

Publisher: Frontiers Media SA

Date: 2011

DOI: 10.3389/FIMMU.2011.00067

Cytokine‐related syndrome following injection of anti‐CD3 monoclonal antibody: Further evidence for transient in vivo T cell activation

Publisher: Wiley

Date: 03-1990

DOI: 10.1002/EJI.1830200308

Abstract: In vivo injection of the hamster anti-murine CD3 monoclonal antibody 145 2C11 into BALB/c mice induces a massive systemic release of several cytokines. Very high circulating levels of tumor necrosis factor are detected both by enzyme-linked immunosorbent assay and L-929 bioassay 90 min following a single injection of 10 micrograms/mouse 145 2C11. Peak circulating levels of exclusively T cell-derived products such as interferon-gamma, interleukin 2 and interleukin 3 are also detected 90 min to 8 h post-injection. Importantly, this cytokine release is transient since none of these cytokines are still present 12 to 24 h post-injection. In parallel to cytokine release, 145 2C11-treated mice (10 micrograms/mouse) exhibit somnolence, hypomotility (quantified by actimetry), hypothermia, diarrhea and piloerection. At this dosage, the physical reaction is not lethal and reverses in all mice by 48 h post-injection. Severe but again reversible anatomopathological changes are also observed: massive cellular depletion, necrosis and edema of lymphoid organs, leakage syndrome and inflammatory cell infiltrates of the lung, cell vacuolization, necrosis and vascular congestion of the liver. All these data are similar to the clinical and immunological manifestations of the OKT3-induced reaction in patients and, thus, provide an invaluable experimental tool to study its mechanisms and explore its prevention.

Microparticles and their emerging role in cancer multidrug resistance

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.CTRV.2011.06.005

Abstract: Drug resistance is a major obstacle to the successful treatment of cancer as tumor cells either fail to reduce in size following chemotherapy or the cancer recurs after an initial response. The phenomenon of multidrug resistance (MDR) is particularly problematic as it involves the simultaneous resistance to numerous chemotherapeutics of different classes. MDR is predominantly attributed to the overexpression of efflux transporters such as P-glycoprotein (P-gp) and the Multidrug Resistance-Associated Protein 1 (MRP1). P-gp and MRP1 are members of the ATP Binding Cassette (ABC) superfamily of transporters and are capable of effluxing many chemotherapeutics out of cancer cells, allowing them to survive the toxic insult. Numerous strategies have been developed over the years to circumvent MDR. Of these, the discovery and implementation of P-gp and MRP1 inhibitors have been most extensively studied. However, these inhibitors have not been able to be used clinically. While research continues in this area, it must also be acknowledged that other avenues must be explored. Recently, the novel 'non-genetic' acquisition of P-gp-mediated MDR by microparticles (MPs) has been reported. MPs are vesicles 0.1-1μm in diameter that are released via plasma membrane blebbing. They are important mediators of inflammation, coagulation and vascular homeostasis. In addition to surface P-gp protein, MPs also carry various nucleic acid species as cargo. This 'non-genetic' intercellular transfer provides an alternative pathway for the cellular acquisition and dissemination of traits and implicates MPs as important mediators in the spread of MDR and provides a novel pathway for the circumvention of MDR.

Technical Advance: Autofluorescence as a tool for myeloid cell analysis

Publisher: Oxford University Press (OUP)

Date: 09-06-2010

DOI: 10.1189/JLB.0310184

Abstract: The autofluorescence of myeloid cell populations is heterogeneous and can be used as a tool for identification and phenotyping of myeloid subsets. Cellular AF is usually considered a hindrance to flow cytometric analysis. Here, we incorporate AF into analysis of complex mixtures of leukocytes. Using a mouse model, we examined cellular AF at multiple excitation and emission wavelengths, and populations with discrete patterns were gated and examined for surface marker expression. In the spleen, all major myeloid populations were identified. In particular, the approach allowed simultaneous characterization of RPM and resident monocytes. When monocytes and RPM were compared, RPM exhibited a phenotype that was consistent with involvement in physiological processes, including expression of genes involved in lipid and iron metabolism. The presence of large amounts of stored ferric iron within RPM enabled purification of these cells using a magnetic-based approach. When adapted for use on leukocytes isolated from a range of other organs, incorporation of AF into analysis allowed identification and isolation of biologically important myeloid populations, including subsets that were not readily identifiable by conventional cytometric analysis.

Anti-parasite effects of cytokines in malaria

Publisher: Elsevier BV

Date: 08-1990

DOI: 10.1016/0165-2478(90)90118-A

Abstract: Cytokines induced during natural malaria infections, e.g., at crisis of a blood infection of Plasmodium cynomolgi, and during clinical paroxysms in human Plasmodium vivax infections, mediate killing of intra-erythrocytic blood stage malaria parasites. These cytokines, TNF and IFN-gamma, require additional, yet unidentified complementary factors that are present in "crisis" and "paroxysm" serum to kill intra-erythrocytic blood stage parasites. In contrast, cytokines, (mainly IFN-gamma) are able to effect killing of intra-hepatic stages of the parasite by themselves independent of serum complementary factors, suggesting that the mechanisms of killing may be different with respect to the two parasite stages. Cytokines also appear to be critical intermediates in mechanisms of clinical disease in malaria. Serum cytokine (TNF) levels and killing effects on blood stage malaria parasites were lower in patients who were exposed to endemic P. vivax malaria who had partial clinical immunity, than in non-immune patients. Evidence suggest that in iduals acquire natural immunity to the disease by avoiding the induction of high levels of cytokines and complementary factors.

Tumor Necrosis Factor and Disease Severity in Children with Falciparum Malaria

Publisher: Massachusetts Medical Society

Date: 15-06-1989

DOI: 10.1056/NEJM198906153202404

Abstract: The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.

Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection

Publisher: American Society for Microbiology

Date: 30-10-2015

DOI: 10.1128/MBIO.01390-15

Abstract: Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV + ) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV + and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly ( times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly ( -fold) greater in HIV + children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV + children exacerbates the pathological features associated with CM. IMPORTANCE There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV + ) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV + than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV + children. Our findings raise the possibility that HIV + children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.

Inhibition of Endothelial Activation: A New Way to Treat Cerebral Malaria?

Publisher: Public Library of Science (PLoS)

Date: 23-08-2005

DOI: 10.1371/JOURNAL.PMED.0020245

Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential.

Publisher: Rockefeller University Press

Date: 03-1991

DOI: 10.1084/JEM.173.3.523

Abstract: Malaria infection crisis, at which the parasitemia drops precipitously and the parasite loses infectivity to the mosquito vector, occurs in many natural malaria systems, and has not been explained. We demonstrate that in a simian malaria parasite (Plasmodium cynomolgi in its natural host, the toque monkey), the loss of infectivity during crisis is due to the death of circulating intraerythrocytic gametocytes mediated by crisis serum. These parasite-killing effects in crisis serum are due to the presence in the serum of cytokines tumor necrosis factor and interferon gamma, which are produced by the host as a result of the malaria infection. The killing activity of each cytokine is absolutely dependent upon the presence of additional, as yet unidentified factor(s) in the crisis serum.

Tumor‐Necrosis Factor and other Cytokines in Cerebral Malaria: Experimental and Clinical Data

Publisher: Wiley

Date: 12-1989

DOI: 10.1111/J.1600-065X.1989.TB00552.X

Abstract: Evidence is presented here that tumor necrosis factor/cachectin (TNF), is of crucial importance in the pathogenesis of cerebral malaria. First, the central lesion of CM, hemorrhagic necrosis of cerebral vessels, corresponds to lesions observed during other pathological conditions associated with high serum TNF levels, such as endotoxemic shock or administration of TNF. Second, in both mouse and human, there is a close correlation between high serum TNF levels and CM. At least in mouse, high TNF levels and CM depend upon T lymphocytes of the CD4+ phenotype. Third, passive immunization against mouse TNF significantly prolongs the survival of P. berghei-infected CBA/Ca mice, and prevents the development of neurologic signs. Treatment with the anti-TNF antibody also prevents hemorrhagic necrosis of brain vessels. Fourth, in the mouse model, a cytokine cascade including at least GM-CSF, IL-3 and IFN-gamma is required for the elevation of TNF level. This cascade appears to involve two components: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Fifth, metabolic parameters of CM and its main lesion in both mouse and human, i.e. the hemorrhagic necrosis of small brain vessels, correspond to the known properties of TNF.

Late administration of monoclonal antibody to leukocyte function‐antigen 1 abrogates incipient murine cerebral malaria

Publisher: Wiley

Date: 09-1991

DOI: 10.1002/EJI.1830210939

Abstract: We analyzed the role of adhesion molecules in the pathogenesis of experimental cerebral malaria (ECM), since tumor necrosis factor (TNF) plays a major role in this condition and has been shown to up-regulate in vitro expression of cell adhesion molecules (CAM), particularly intercellular CAM-1 (ICAM-1). We found increased expression of ICAM-1 on brain endothelial cells from mice with ECM. Treatment with monoclonal antibodies (mAb) directed against leukocyte function-antigen 1 (LFA-1, the ligand of ICAM-1) on days 6, 8 and 10 almost totally prevented ECM, while decreasing blood TNF levels. To exclude the possibility that the effects of anti-LFA-1 mAb resulted from an even partial inhibition of TNF overproduction, mice with signs of imminent death (hypothermia and neurologic defects) were treated with the anti-LFA-1 mAb, with dramatically protective effect. In contrast, injection of anti-ICAM-1 mAb on day 6 caused rapid death, while it was innocuous in normal mice. An mAb directed against complement receptor type 3 (CR3) was ineffective, as were injections of soluble human ICAM-1. These results suggest that adhesion of LFA-1+ cells to endothelial cells, stimulated by TNF to express high levels of ICAM-1, is critical in the pathogenesis of ECM. Emergency therapy at interfering with cytoadherence could be considered in the treatment of cerebral malaria in man, in which high blood TNF levels are also observed.

Differential plasma microvesicle and brain profiles of microRNA in experimental cerebral malaria

Publisher: Springer Science and Business Media LLC

Date: 11-05-2018

DOI: 10.1186/S12936-018-2330-5

Microvesiculation and cell interactions at the brain–endothelial interface in cerebral malaria pathogenesis

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.PNEUROBIO.2010.01.007

Abstract: Cerebral malaria (CM) is still a major world health problem whose pathogenic mechanisms remain incompletely understood. After reviewing some particularities of anti-malarial immunity, we focus here on the neurovascular aspects of CM. We specifically address the central role of endothelial activation and alteration in disease pathogenesis. We discuss the respective roles of "mediator-induced" versus "host cell-induced" mechanisms of endothelial alteration. The former include cytokines, chemokines and their receptors, while the latter encompass cells located inside and outside the vessel, notably glial cells. We also present evidence for a pathogenic role for membrane microparticles (MP) in CM, based on studies in African patients and in a recognised mouse model. Intervention studies on MP production, via either gene knockout or pharmacological inhibition, can prevent the neurological syndrome and its associated mortality, suggesting potential new therapeutic avenues.

Demonstration of anti-disease immunity to Plasmodium vivax malaria in Sri Lanka using a quantitative method to assess clinical disease.

Publisher: American Society of Tropical Medicine and Hygiene

Date: 02-1998

DOI: 10.4269/AJTMH.1998.58.204

Abstract: Clinical immunity to malaria was studied by quantifying the intensity of symptoms as well as by measurement of several hematologic indicators of pathology (the erythrocyte sedimentation rate [ESR], serum bilirubin, reticulocyte count, plasma tumor necrosis factor-alpha [TNF-alpha], and blood glucose levels) in 39 Plasmodium vivax malaria patients exposed to endemic malaria in southern Sri Lanka, and for comparison in 43 nonimmune patients who were residents of nonmalarious regions of the country. The intensity of 11 symptoms was scored numerically in all patients using a questionnaire. This clinical score was validated by introducing internal controls to the questionnaire, and by correlating it with the underlying pathology. Both the intensity of clinical disease as well as the degree of underlying pathology were found to be significantly lower in endemic area patients (mean clinical score = 8.8, median ESR = 8 mm) compared with the nonendemic area patients (mean clinical score = 19.0, median ESR 31.5 mm). Endemic area patients also had lower parasite densities (mean = 0.06%) than those from the nonendemic area (0.12%) (P < 0.05). However, at any parasite density, both clinical disease and pathology were significantly less in the endemic area patients (P < 0.001, for both clinical score and ESR), indicating that the clinical immunity seen in the endemic area patients was a true tolerance of parasites. Although plasma TNF-alpha levels were elevated in both groups of patients, they were significantly higher in the nonendemic area patients than in patients from the endemic area (P < 0.01). Furthermore, at comparable levels of plasma TNF-alpha, nonendemic area patients had both a higher intensity of clinical disease and an underlying pathology than those from the endemic area, suggesting that if TNF-alpha is indeed a mediator of clinical disease, the endemic area patients may be tolerant to its effects. Hypoglycemia was not observed in any of these P. vivax patients despite some with high levels of plasma TNF-alpha.

ABCA1 Gene Deletion Protects against Cerebral Malaria

Publisher: Elsevier BV

Date: 2005

DOI: 10.1016/S0002-9440(10)62253-5

Rickettsia prowazekii infection of endothelial cells increases leukocyte adhesion through αvβ3 integrin engagement

Publisher: Elsevier BV

Date: 12-2009

DOI: 10.1111/J.1469-0691.2008.02675.X

The effect of non-specific tight junction modulators on the transepithelial transport of poorly permeable drugs across airway epithelial cells

Publisher: Informa UK Limited

Date: 24-11-2017

DOI: 10.1080/1061186X.2016.1258703

Tumor Necrosis Factor and Interleuktn-1 in the Serum of Children with Severe Infectious Purpura

Publisher: Massachusetts Medical Society

Date: 18-08-1988

DOI: 10.1056/NEJM198808183190703

Abstract: Diagnosis of esophageal squamous cell carcinoma (SCC) may improve with early diagnosis. Currently it is difficult to diagnose SCC in the early stage because there is a limited number of tumor markers available. Fifty-two esophageal SCC SEREX antigens were identified by SEREX (serological identification of antigens by recombinant cDNA expression cloning) using a cDNA phage library and sera of patients with esophageal SCC. Sequence analysis revealed that three of these antigens were similar in amino acid sequences, and they were designated as ECSA (esophageal carcinoma SEREX antigen)-1, -2 and -3. The ECSA family was also similar to an EST clone, hepatocellular carcinoma-associated antigen 25a (HCA25a). Serum antibody levels to ECSA-1, -2 and -3 were significantly higher in patients with esophageal SCC than in healthy donors. Based on the conserved amino acid sequences, three peptides were synthesized and used for enzyme-linked immunosorbent assays (ELISA). The serum antibody levels against one of these peptides were significantly higher in patients with esophageal SCC. This peptide sequence was also conserved in FAM119A, GOSR1 and BBS5, suggesting that these are also ECSA family members. Reverse transcription followed by quantitative PCR analysis showed that the mRNA expression levels of ECSA-1, -2 and -3 and FAM119A but not of HCA25a, GOSR1 and BBS5 were frequently elevated in esophageal SCC tissues. We have identified a new gene family designated ECSA. Serum antibodies against the conserved domain of the ECSA family may be a promising tumor marker for esophageal SCC.

Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content

Publisher: Springer Science and Business Media LLC

Date: 05-12-2016

DOI: 10.1038/SREP37871

Abstract: Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection responsible for thousands of deaths in children in sub-Saharan Africa. CM pathogenesis remains incompletely understood but a number of effectors have been proposed, including plasma microparticles (MP). MP numbers are increased in CM patients’ circulation and, in the mouse model, they can be localised within inflamed vessels, suggesting their involvement in vascular damage. In the present work we define, for the first time, the protein cargo of MP during experimental cerebral malaria (ECM) with the overarching hypothesis that this characterisation could help understand CM pathogenesis. Using qualitative and quantitative high-throughput proteomics we compared MP proteins from non-infected and P . berghei ANKA-infected mice. More than 360 proteins were identified, 60 of which were differentially abundant, as determined by quantitative comparison using TMT TM isobaric labelling. Network analyses showed that ECM MP carry proteins implicated in molecular mechanisms relevant to CM pathogenesis, including endothelial activation. Among these proteins, the strict association of carbonic anhydrase I and S100A8 with ECM was verified by western blot on MP from DBA/1 and C57BL/6 mice. These results demonstrate that MP protein cargo represents a novel ECM pathogenic trait to consider in the understanding of CM pathogenesis.

Plasmodium falciparum Adhesion on Human Brain Microvascular Endothelial Cells Involves Transmigration-Like Cup Formation and Induces Opening of Intercellular Junctions

Publisher: Public Library of Science (PLoS)

Date: 29-07-2010

DOI: 10.1371/JOURNAL.PPAT.1001021

The role of adhesion molecules, αvβ3, αvβ5 and their ligands in the tumor cell and endothelial cell adhesion

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 12-2007

DOI: 10.1097/CEJ.0B013E3280145C00

Tumour necrosis factor, interleukin-6, and malaria

Publisher: Elsevier BV

Date: 05-1991

DOI: 10.1016/0140-6736(91)91745-G

Endogenous TNF-α Modulates the Proliferation of Rat Mesangial Cells and Their Prostaglandin E2 Synthesis

Publisher: Elsevier BV

Date: 09-1995

DOI: 10.1006/MVRE.1995.1049

Abstract: Mesangial cells (MC) are one cellular source of tumor necrosis factor alpha (TNF) within the kidney as shown by experimental stimulation with endotoxin. TNF was shown to increase MC synthesis of prostaglandins E2 (PGE2) which down regulate MC proliferation. The involvement of endogenous TNF as an autocrine factor to control MC proliferation is unknown. This role was evaluated in vitro by addition of anti-TNF immunoglobulins and soluble TNF receptor-I (sTNF-RI) on rat MC. Anti-TNF immunoglobulins and sTNF-RI induced a dose-dependent increase of cell proliferation when the cells were quiescent in 0.5% FCS P = 0.002). No effect was found when the cells were growing in 10% FCS (P = 0.113). Incubation of MC with anti-TNF immunoglobulins resulted in a dose-dependent decrease of PGE2 release. In order to investigate if the effect of TNF on MC proliferation was mediated by the decrease of PGE2 release, PGE2 was added to the culture medium at concentrations of 0.1 to 10 micrograms/ml in conjunction with anti-TNF immunoglobulins. PGE2 did not modify the proliferation induced by anti-TNF immunoglobulins. We conclude that anti-TNF immunoglobulins and sTNF-RI promoted MC DNA synthesis and influenced their PGE2 release by blocking the endogenous TNF. The mechanism of action on DNA synthesis was not mediated by PGE2. This indicates that endogenous TNF has a substantial role in the control of resting mesangial cells.

Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions.

Publisher: Rockefeller University Press

Date: 03-1991

DOI: 10.1084/JEM.173.3.673

Abstract: We examined the role of cytokines in the cutaneous response to the application of trinitrochlorobenzene (TNCB) in both nonsensitized and sensitized mice, i.e., in the irritant reaction (IR) and contact hypersensitivity reactions (CH). When administered immediately before challenge, anti-tumor necrosis factor (TNF) antibody abrogated the ear swelling response in CH antibody directed against interferon gamma or antibodies to both granulocyte/macrophage colony-stimulating factor and interleukin 3 (IL-3) had a partial inhibitory effect anti-IL-2 receptor antibody had no effect. Anti-TNF prevented the various features of the CH, as seen on histological sections, e.g., leukocyte infiltration and hemorrhages within the dermis and keratinocytes necrosis. Anti-TNF antibody also prevented the IR. The presence of TNF mRNA was evaluated on Northern blots TNF-alpha mRNA was detectable in an untreated ear, increased after the application of TNCB in nonsensitized mice, and was highest in sensitized mice. TNF mRNA accumulation, which was evident 0.5 h after hapten application and lasted greater than 72 h, was abolished by treatment with anti-TNF antibody, thus suggesting an auto- lification of TNF production. The cellular origin of TNF mRNA was explored by in situ hybridization basal keratinocytes showed the highest labeling, but TNF mRNA was also detectable in cells of the dermal infiltrate. After hapten (TNCB) application at sites susceptible (the ear) or resistant (the foot pad) to CH or IR, a close correlation was observed between TNF mRNA accumulation and the intensity of the inflammatory reaction. The major role played by TNF in both the CH and the IR explains the histologically similar aspects of these reactions and the extreme variability of these reactions at various anatomical sites.

Stem Cell-Derived Extracellular Vesicles for Treating Joint Injury and Osteoarthritis

Publisher: MDPI AG

Date: 14-02-2019

DOI: 10.3390/NANO9020261

Abstract: Extracellular vesicles (EVs) are nanoscale particles secreted by almost all cell types to facilitate intercellular communication. Stem cell-derived EVs theoretically have the same biological functions as stem cells, but offer the advantages of small size, low immunogenicity, and removal of issues such as low cell survival and unpredictable long-term behaviour associated with direct cell transplantation. They have been an area of intense interest in regenerative medicine, due to the potential to harness their anti-inflammatory and pro-regenerative effects to induce healing in a wide variety of tissues. However, the potential of using stem cell-derived EVs for treating joint injury and osteoarthritis has not yet been extensively explored. The pathogenesis of osteoarthritis, with or without prior joint injury, is not well understood, and there is a longstanding unmet clinical need to develop new treatments that provide a therapeutic effect in preventing or stopping joint degeneration, rather than merely relieving the symptoms of the disease. This review summarises the current evidence relating to stem cell-derived EVs in joint injury and osteoarthritis, providing a concise discussion of their characteristics, advantages, therapeutic effects, limitations and outlook in this exciting new area.

Murine cerebral malaria: the whole story

Publisher: Elsevier BV

Date: 06-2010

DOI: 10.1016/J.PT.2010.03.006

Platelet‐Induced Clumping ofPlasmodium falciparum–Infected Erythrocytes from Malawian Patients with Cerebral Malaria—Possible Modulation In Vivo by Thrombocytopenia

Publisher: Oxford University Press (OUP)

Date: 2008

DOI: 10.1086/523761

Repeated Endotoxin Treatment Decreases Immune and Hypothalamo-Pituitary-Adrenal Axis Responses: Effects of Orchidectomy and Testosterone Therapy

Publisher: S. Karger AG

Date: 1995

DOI: 10.1159/000127024

Abstract: It is known that in vivo administration of bacterial endotoxin activates immune cells to release cytokines, these substances in turn enhancing hypothalamo-pituitary-adrenal (HPA) axis function additional evidence supports the existence of an immune-neuroendocrine sexual dimorphism. In the present study, we investigated: (1) the in vivo response of both the HPA and the immune systems to single and repeated endotoxin administrations in mice, and (2) whether testosterone possesses a modulatory effect on neuroendocrine-immune function under endotoxemia. For these purposes, adult male BALB/c mice were orchidectomized (Odx) or sham-operated and injected s.c., on alternate days, with either corn oil alone (Odx and Sham) or containing 20 micrograms of testosterone (Odx+T) until animals were killed. One week after surgery, different groups of mice were treated i.p. with bacterial lipopolysaccharide (LPS 25 micrograms per mouse) in a single (day 1, D1) or repeated (at 24-hour intervals for 5 consecutive days) form. Animals were decapitated (on D1, D3 and D5 of the treatment) 2 h after the last injection of either vehicle alone or containing LPS (the two groups were run in parellel). Trunk blood was collected and the whole medial basal hypothalamus (wMBH), the anterior pituitary (AP) and adrenal glands were dissected. Plasma tumor necrosis factor-alpha (TNF alpha), ACTH and corticosterone (B) concentrations as well as wMBH CRH, AP ACTH and adrenal B contents were determined by specific assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum tumor necrosis factor and interleukin 1 in leprosy and during lepra reactions

Publisher: Elsevier BV

Date: 04-1992

DOI: 10.1016/0090-1229(92)90088-6

Abstract: Tumor necrosis factor--alpha (TNF), one of the mediators of septic shock, has a role in the immunopathological complications of several infections. However, its role in leprosy is yet unclear. In this study, serum TNF and IL-1 levels in 64 patients spread over the spectrum of leprosy [lepromatous leprosy (LL), 30 borderline lepromatous, 12 borderline borderline, 8 and borderline tuberculoid-tuberculoid leprosy, 14] were measured at the time of admission. Elevated levels of TNF ranging from 15 to 4500 pg/ml were detected in lepromatous leprosy cases (399 +/- 189) and low levels ranging from 15 to 160 pg/ml were detected in the tuberculoid form of leprosy. Patients undergoing type 1 and type 2 lepra reactions also exhibited high TNF levels of 15-2100 pg/ml. Of the 14 clinically healthy in iduals studied, 3 showed TNF levels of 15, 50, and 58 pg/ml. Interleukin 1-beta (IL-1) levels were found to be significantly higher in LL cases (70-5000 pg/ml) (328 +/- 184) in comparison to other groups or normal controls (9 +/- 3). The coefficient of correlation between TNF and IL-1 levels was statistically significant in LL and reaction cases (r = 0.96, P less than 0.001). These patients were followed up as outpatients for a period of 1 year. It was observed that 4 out of 8 patients with TNF levels greater than 100 pg/ml went into lepra reactions between 2 and 6 months after entry into the study, whereas only 5 out of 56 with less than 100 pg/ml went into mild lepra reactions (chi 2 = 9.7, P less than 0.01). Determination of TNF and IL-1 levels thus seems to have a prognostic significance in terms of lepra reaction in patients.

Crossing the wall: The opening of endothelial cell junctions during infectious diseases

Publisher: Elsevier BV

Date: 07-2013

DOI: 10.1016/J.BIOCEL.2013.03.010

Abstract: Vascular endothelial cells (ECs) form a barrier that plays a crucial role in the health and integrity of tissues by regulating the passage of molecules, liquids and immune cells. Dysfunctions or disruption of this barrier leads to edema, inflammation, and associated pathologies. During infection, ECs control transmigration of cells by a complex system of molecules. However pathogens can hijack this pathway to invade ECs and/or tissues. They can also trigger the opening of intercellular junction, apoptosis of ECs or activation of the immune system, which in turn lead to the destruction of the endothelial wall and subsequent edema. Activation of immune cells by pathogens can also enhance the destruction of EC and edema. The review summarizes the state-of-the-art knowledge on the key steps of the complex interactions between the endothelial wall, pathogens, and the immune system that lead to the opening of junctions and/or destruction of the wall, enhancing pathology. A better understanding of these points will allow the development of adjunctive treatments to be used in combination with therapies targeting pathogens, with the aim of protecting the wall and improving the recovery of patients with severe infectious diseases.

Dengue virus infection of human microvascular endothelial cells from different vascular beds promotes both common and specific functional changes

Publisher: Wiley

Date: 2005

DOI: 10.1002/JMV.20532

Abstract: Dengue shock syndrome (DSS), the major life threatening outcome of severe dengue disease, which occurs in some patients in the course of dengue infection, is the consequence of plasma leakage in the microvascular territories. Data from clinical and in vitro studies suggest that an inadequate immunological response is partly responsible for the pathophysiology of DSS, but few is known concerning the consequences of direct infection of endothelial cells by dengue virus per se. In this study, an attempt was made to study the response of two microvascular human cell lines originating, respectively, from liver and dermis to infection by a dengue type 2 virus, by analyzing the virus-induced modulation of functional markers. It is shown that the two microvascular cell lines exhibit both common and specific behaviors upon infection. In particular, LSEC and HMEC-1 replicate efficiently the low-passage virus and respond to infection by over-producing inflammatory mediators involved in the cross talk with circulating immune cells. However, direct infection modulates differently the cell surface expression of molecules critically involved in the interactions between endothelial and inflammatory cells. ICAM-1 and HLA-I are up regulated as a consequence of infection in LSEC whereas direct infection results in downregulation of ICAM-1 in HMEC-1. The present results show that infection of human microvascular cells by unadapted dengue virus results in both common and specific activation patterns depending likely on the tissue origin of the cells, thus suggesting that endothelia from different territories may contribute differently to the pathophysiological events in the course of dengue infection.

Stable thrombus formation on irradiated microvascular endothelial cells under pulsatile flow: Pre-testing annexin V-thrombin conjugate for treatment of brain arteriovenous malformations

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.THROMRES.2018.05.016

Abstract: Our goal is to develop a vascular targeting treatment for brain arteriovenous malformations (AVMs). Externalized phosphatidylserine has been established as a potential biomarker on the endothelium of irradiated AVM blood vessels. We hypothesize that phosphatidylserine could be selectively targeted after AVM radiosurgery with a ligand-directed vascular targeting agent to achieve localized thrombosis and rapid occlusion of pathological AVM vessels. The study aim was to establish an in vitro parallel-plate flow chamber to test the efficacy of a pro-thrombotic conjugate targeting phosphatidylserine. Conjugate was prepared by Lys-Lys cross-linking of thrombin with the phosphatidylserine-targeting ligand, annexin V. Cerebral microvascular endothelial cells were irradiated (5, 15, and 25 Gy) and after 1 or 3 days assembled in a parallel-plate flow chamber containing whole human blood and conjugate (1.25 or 2.5 μg/mL). Confocal microscopy was used to assess thrombus formation after flow via binding and aggregation of fluorescently-labelled platelets and fibrinogen. The annexin V-thrombin conjugate induced rapid thrombosis (fibrin deposition) on irradiated endothelial cells under shear stress in the parallel-plate flow device. Unconjugated, non-targeting thrombin did not induce fibrin deposition. A synergistic interaction between radiation and conjugate dose was observed. Thrombosis was greatest at the highest combined doses of radiation (25 Gy) and conjugate (2.5 μg/mL). The parallel-plate flow system provides a rapid method to pre-test pro-thrombotic vascular targeting agents. These findings validate the translation of the annexin V-thrombin conjugate to pre-clinical studies.

Interplay of extracellular vesicles and other players in cerebral malaria pathogenesis

Publisher: Elsevier BV

Date: 02-2019

DOI: 10.1016/J.BBAGEN.2018.10.012

Abstract: Malaria is a serious parasitic infection affecting millions of people worldwide each year. Cerebral malaria is the most severe complication of Plasmodium infections, predominantly affecting children. Extracellular vesicles are essential mediators of intercellular communication and include apoptotic bodies, microvesicles and exosomes. Microvesicle numbers increase during disease pathogenesis and inhibition of their release can prevent brain pathology and mortality. We explore the current knowledge on microvesicles and exosomes in cerebral malaria pathogenesis. Microvesicles and exosomes are implicated in cerebral malaria pathogenesis, in the modulation of host immunity to Plasmodium, and in cell-cell communication. Blocking their production is protective in models of cerebral malaria, both in vivo and in vitro. While anti-malarial treatments exist to combat Plasmodium infections, increasing drug resistance presents a major challenge. In order to improve diagnosis and treatment outcomes, further research is required to better appreciate extracellular vesicle involvement in cerebral malaria.

Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/1043-4666(93)90024-Y

Abstract: We explored the role of interleukin 1 (IL-1) in two models of pulmonary fibrosis (PF), elicited in mice by the intra-tracheal instillation of bleomycin or silica. In both models, administration of IL-1 receptor antagonist (IL-1ra) by an osmotic minipump implanted i.p., at a rate of 0.5 microgram/h, completely prevented the collagen deposition, as evaluated by the lung hydroxyproline content on day 15 after instillation. IL-1ra had little or no influence on the number of cells recovered from the broncho-alveolar lavage. Study of histological sections suggests that IL-1ra globally decreased the proportion of damaged lung and particularly in silica the formation of nodules with a rich content in collagen fibrils. IL-1ra was also effective in reducing the lung hydroxyproline content when given on day 25 after instillation of bleomycin or silica, indicating that it may reverse established PF. This study indicates that IL-1ra might be useful for the treatment of incipient or established pulmonary fibrosis.

Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients

Publisher: SAGE Publications

Date: 11-07-2016

DOI: 10.1177/1352458516636959

Abstract: No molecular marker can monitor disease progression and treatment efficacy in multiple sclerosis (MS). Circulating microparticles represent a potential snapshot of disease activity at the blood brain barrier. To profile plasma microparticles by flow cytometry in MS and determine how fingolimod could impact endothelial microparticles production. In non-treated MS patients compared to healthy and fingolimod-treated patients, endothelial microparticles were higher, while B-cell-microparticle numbers were lower. Fingolimod dramatically reduced tumour necrosis factor (TNF)-induced endothelial microparticle release in vitro. Fingolimod restored dysregulated endothelial and B-cell-microparticle numbers, which could serve as a biomarker in MS.

Gene‐Expression Profiling Discriminates between Cerebral Malaria (CM)–Susceptible Mice and CM‐Resistant Mice

Publisher: Oxford University Press (OUP)

Date: 15-01-2006

DOI: 10.1086/498579

Abstract: The development of cerebral malaria (CM) in mice with Plasmodium berghei ANKA infection is under genetic control. Brain gene-expression patterns were investigated in well-defined genetically CM-resistant (CM-R BALB/c and DBA/2) and CM-susceptible (CM-S C57BL/6 and CBA/J) mice by use of cDNA microarrays. By combining transcriptional profiling with rigorous statistical methods and cluster analysis, we identified a set of 69 genes that perfectly discriminated between mouse strains and between CM-R and CM-S mice. The analysis of gene ontological terms revealed that the genes that clustered and were related to susceptibility to CM preferentially belonged to some biological process classes, such as those pertaining to immune responses. Using a false discovery rate of 5% and the Welch t test, we identified 31 genes with consistent differential expression between CM-R and CM-S mice. These data indicate that microarray analysis may be useful for identification of candidate genes that are potentially responsible for resistance or susceptibility to mouse CM and suggest that candidate genes identified in mice could be specifically tested in humans for an association with disease severity.

NEW SYNTHETIC SULFATED OLIGOSACCHARIDES PROLONG SURVIVAL OF CARDIAC XENOGRAFTS BY INHIBITING RELEASE OF HEPARAN SULFATE FROM ENDOTHELIAL CELLS

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-1996

DOI: 10.1097/00007890-199605150-00003

Abstract: Binding of recipient natural antibodies to the endothelium of the graft, complement activation, endothelial cell activation, and microvascular thrombosis are major events in the hyperacute rejection of organ xenografts. The aim of this study was to investigate the effects of two new synthetic sulfated oligosaccharides (A and B) on the survival of discordant cardiac xenografts in the guinea pig-to-rat model. In untreated recipients, hyperacute rejection occurred in 5 min (median range, 4-6 min) and immunohistological analysis of all the grafts revealed deposition of IgM and C3 along the endothelium. Administration of oligosaccharides A and B prior to revascularization prolonged the survival of xenografts in a dose-dependent manner, up to 113 min (median range, 42-145 min) and 86 min (median range, 35-108 min), respectively, when doses of 20 mg/kg were used. There were no bleeding complications. Histological examination of the rejected grafts showed a picture of hyperacute rejection, with no difference in IgM and C3 deposition as compared with the untreated animals. In cell culture experiments, the release of heparan sulfate from guinea pig cardiac endothelial cells induced by rat serum was inhibited by both saccharides in a dose-dependent manner. The results indicate that these new synthetic sulfated oligosaccharides are effective for prolongation of discordant xenograft survival, possibly by interfering with endothelial cell activation. Such substances may be of value in other xenotransplant combinations.

Cascade modulation by anti‐tumor necrosis factor monoclonal antibody of interferon‐γ, interleukin 3 and interleukin 6 release after triggering of the CD33/T cell receptor activation pathway

Publisher: Wiley

Date: 10-1991

DOI: 10.1002/EJI.1830211009

Abstract: In addition to being potent immunosuppressants, anti-CD3 monoclonal antibodies (mAb) are powerful mitogens in both humans and mice. The first antibody injection consistently induced an initial monocyte-dependent T cell activation with subsequent release of both monocyte- and T cell-derived cytokines [mainly tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL) 2, IL 3 and IL 6) into the circulation. This cytokine release is associated with a self-limiting, often severe, acute physical reaction in both patients and mice. We report here that a single injection of anti-TNF mAb prior to anti-CD3 administration not only neutralizes the biological activity of TNF but also strongly affects the release of other cytokines, with notably an up-regulation of IFN-gamma release and a down-regulation of IL 3 and IL 6 release. Conversely, pretreatment with anti-IFN-gamma mAb increases IL 3 and IL 6 production but does not affect TNF levels. Taken together, these data point to a pivotal role of IFN-gamma in the anti-CD3-induced cytokine cascade and reveal new regulatory pathways between TNF and IFN-gamma. With regard to the clinical implications of these findings, as anti-TNF mAb prevents anti-CD3-induced sickness in mice, whereas anti-IFN-gamma does not, such a therapeutic approach might be of value in OKT3-treated patients.

Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis

Publisher: Springer Science and Business Media LLC

Date: 03-1990

DOI: 10.1038/344245A0

Abstract: The deposition of silica particles in the lung of man or experimental animals leads to silicosis, a disease of progressive respiratory failure caused by a fibrotic reaction. It has long been suspected that the phagocytosis of silica by pulmonary macrophages induces the secretion of fibrogenic factors. Several potentially fibrogenic cytokines released by macrophages have been identified, including interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF), platelet-derived growth factor, basic fibroblast growth factor and transforming growth factor-beta (TGF-beta). Here we show that TNF plays an important part in silica-induced pulmonary fibrosis in mice in that (1) a single instillation of silica leads to a marked increase in the level of lung TNF messenger RNA which lasts for greater than 70 days, while there are no obvious changes in the amounts of IL-1 alpha or TGF-beta mRNAs and (2) silica-induced collagen deposition is almost completely prevented by anti-TNF antibody, but is significantly increased by continuous infusion of mouse recombinant TNF.

Circulating plasma receptors for tumour necrosis factor in Malawian children with severe falciparum malaria

Publisher: Elsevier BV

Date: 11-1993

DOI: 10.1016/S1043-4666(05)80011-0

Abstract: Tumour necrosis factor (TNF) concentrations are increased in the plasma during a malarial illness, and are highest in patients with severe or fatal disease. We have studied the plasma concentrations of two soluble receptors (sTNF-R1 and sTNF-R2), which act as binding proteins for TNF, in children with falciparum malaria. In 52 Malawian children with malaria, plasma concentrations of both sTNF-R1 (mean (S.D.) 4759(2552) pg/ml) and sTNF-R2 (59077(37102) pg/ml) were greatly increased when compared with levels of convalescence (sTNF-R1 718(68), and sTNF-R2 8015(7021) pg/ml), and in controls without malaria (486(1353) and 4380(2168)). Concentrations of both receptors correlated with plasma levels of TNF measured by immunoradiometric assay, but not with those of another cytokine, IL-6. The mean plasma concentrations of both immunoreactive TNF and soluble TNF receptors were greater in patients with cerebral malaria than those with uncomplicated malaria. Despite high levels of immunoreactive TNF in the plasma of patients acutely ill with malaria, no bioactive TNF could be detected in these patients by the WEHI cell bioassay. Soluble TNF receptors are present in greatly increased concentrations in the plasma of patients with malaria and may play a role in mediating or modulating the pathogenetic effects of the cytokine.

Modulation of the transcripts for tumor necrosis factor‐α and its receptors in vivo

Publisher: Wiley

Date: 03-1994

DOI: 10.1002/EJI.1830240342

Abstract: We investigated the effects of a single bacterial lipopolysaccharide (LPS) injection in vivo on the gene expression of tumor necrosis factor-alpha (TNF) and its receptors: TNF receptor type I (TNF-R 55 kDa or TNF-R1) and TNF receptor type II (TNF-R 75 kDa or TNF-R2) in various tissues and white blood cells. While TNF mRNA rapidly accumulated in most tissues, TNF-R1 and TNF-R2 mRNA levels were found to be differentially regulated in lung, spleen, lymph nodes and white blood cells. In most cases, TNF-R mRNA levels did not parallel TNF mRNA levels. These observations indicate that TNF-R of both types of capable of modulating the host response to LPS, not only by shedding of their extracellular domains, but also by strict regulation of their gene expression.

Experimental cerebral malaria: Possible new mechanisms in the TNF-induced microvascular pathology

Publisher: Springer Science and Business Media LLC

Date: 1995

DOI: 10.1007/BF01615662

Cooperation between β‐ and γ‐cytoplasmic actins in the mechanical regulation of endothelial microparticle formation

Publisher: Wiley

Date: 16-11-2012

DOI: 10.1096/FJ.12-216531

Abstract: Elevated endothelial microparticle (MP) levels are observed in numerous diseases, increasingly supporting roles as effectors and valuable markers of vascular dysfunction. While a contractile role for the actin cytoskeleton has been implicated in vesiculation, i.e., MP production, the precise interactions and mechanisms of its constituents, β- and γ-cytoplasmic actins, is unknown. Human cerebral microvascular endothelial cells were stimulated with known agonists, and vesiculation development was monitored by scanning electron microscopy (SEM) and flow cytometry. These data in combination provide new insight into the kinetics, patterns of vesiculating cell recruitment, and degrees of response specific to stimuli. Reorganization of β- and γ-actins, F-actin, vinculin, and talin accompanied significant MP release. β-Actin redistribution into basal stress fibers following stimulation was associated with increased apically situated actin-rich particulate structures, which in turn directly correlated with electron-lucent membrane protrusions observed by SEM. Y-27632 Rho-kinase inhibition abolished basal β-actin fiber formation, minimizing apically associated actin-rich structures, significantly reducing membrane protrusions and MP release to near basal levels. Cytoskeletal protein expression and distribution varied between MPs and mother cells, as determined by Western blot. These data strongly suggest that β-actin plays an active facilitative role in agonist-induced protuberance formation, through mechanical interactions with newly described actin-rich structures.

Bridging and Clumping: Investigating Platelet Interactions with P. falciparum-Infected Red Blood Cells and Endothelial Cells in Cerebral Malaria

Publisher: Springer US

Date: 2022

DOI: 10.1007/978-1-0716-2189-9_38

Abstract: The methods presented in this chapter describe how to perform ex vivo clumping and in vitro bridging assays in the context of cerebral malaria. Both the protocols are detailed, and emphasis is made on how to prepare platelet suspensions suitable to each technique, including description of specific buffers and reagents to minimize the risk of aggregation while maintaining the platelet properties.

Assaying tumor necrosis factor concentrations in human serum a WHO International Collaborative Study

Publisher: Elsevier BV

Date: 1995

DOI: 10.1016/0022-1759(95)00028-9

Abstract: A collaborative study involving several international research groups was conducted in order to test the validity and reproducibility of tumor necrosis factor-alpha (TNF) measurements in serum. 58 serum s les, nine of them spiked with recombinant human TNF, were aliquoted and distributed blindly to 11 different laboratories. 20 s les were obtained from cerebral malaria patients, 20 from septic shock patients, eight from patients with rheumatoid arthritis and ten from normal blood donors. The serum s les were assayed for TNF using various immunoassays (ELISA), radioimmunoassays (RIA) and bioassays. Interassay coefficient of variance was analysed. Substantial differences were observed on terms of sensitivity and results obtained with the different commercial and in-house assays. The level of sensitivity was highest with ELISAs and bioassays. RIAs yielded the highest concentrations of TNF in the same s les as compared to those obtained by ELISAs and bioassays. These data emphasize the necessity of establishing international standards for cytokine assays in order to render the interpretation of biological and medical data more reliable.

The Endothelium in Cerebral Malaria: Both a Target Cell and a Major Player

Publisher: Cambridge University Press

Date: 03-09-2007

DOI: 10.1017/CBO9780511546198.143

Interleukin‐10 modulates susceptibility in experimental cerebral malaria

Publisher: Wiley

Date: 08-1997

DOI: 10.1046/J.1365-2567.1997.00290.X

Abstract: In this study, we examined the effects of interleukin-10 (IL-10) on the outcome of experimental cerebral malaria (CM), a lethal neurological syndrome that occurs in susceptible strains of mice after infection with Plasmodium berghei ANKA (PbA). Constitutive IL-10 mRNA levels were significantly higher in the spleen and brain of resistant animals. In vivo neutralization of endogenous IL-10 in CM-resistant mice induced the neurological syndrome in 35.7% of these mice, as opposed to 7.7% in controls. IL-10 inhibited PbA antigen-specific interferon-gamma (IFN-gamma) production in vitro but not tumour necrosis factor (TNF) serum levels in vivo. Susceptible mice, on the other hand, were significantly protected against CM when injected with recombinant IL-10. Overall, our findings suggest that IL-10 plays a protective role against experimental cerebral malaria.

Immuno-analysis of microparticles: probing at the limits of detection

Publisher: Springer Science and Business Media LLC

Date: 10-11-2015

DOI: 10.1038/SREP16314

Abstract: Microparticle (MP) research is clouded by debate regarding the accuracy and validity of flow cytometry (FCM) as an analytical methodology, as it is influenced by many variables including the pre-analytical conditions, instruments physical capabilities and detection parameters. This study utilises a simplistic in vitro system for generating MP and through comparative analysis with immuno-electron microscopy (Immuno-EM) assesses the strengths and limitations of probe selection and high-sensitivity FCM. Of the markers examined, MP were most specifically labelled with phosphatidylserine ligands, annexin V and lactadherin, although only ~60% MP are PS positive. Whilst these two ligands detect comparable absolute MP numbers, they interact with the same population in distinct manners annexin V binding is enhanced on TNF induced MP. CD105 and CD54 expression were, as expected, consistent and enhanced following TNF activation respectively. Their labelling however accounted for as few as 30–40% of MP. The greatest discrepancies between FCM and I-EM were observed in the population solely labelled for the surface antigen. These findings demonstrate that despite significant improvements in resolution, high-sensitivity FCM remains limited in detecting small-size MP expressing low antigen levels. This study highlights factors to consider when selecting endothelial MP probes, as well as interpreting and representing data.

T cells and malaria: is Th1 cell activation a prerequisite for pathology?

Publisher: Elsevier BV

Date: 1994

DOI: 10.1016/S0923-2494(94)80175-4

Delayed Mortality and Attenuated Thrombocytopenia Associated with Severe Malaria in Urokinase- and Urokinase Receptor-Deficient Mice

Publisher: American Society for Microbiology

Date: 07-2000

DOI: 10.1128/IAI.68.7.3822-3829.2000

Abstract: We explored the role of urokinase and tissue-type plasminogen activators (uPA and tPA), as well as the uPA receptor (uPAR CD87) in mouse severe malaria (SM), using genetically deficient (−/−) mice. The mortality resulting from Plasmodium berghei ANKA infection was delayed in uPA −/− and uPAR −/− mice but was similar to that of the wild type (+/+) in tPA −/− mice. Parasitemia levels were similar in uPA −/− , uPAR −/− , and +/+ mice. Production of tumor necrosis factor, as judged from the plasma level and the mRNA levels in brain and lung, was markedly increased by infection in both +/+ and uPAR −/− mice. Breakdown of the blood-brain barrier, as evidenced by the leakage of Evans Blue, was similar in +/+ and uPAR −/− mice. SM was associated with a profound thrombocytopenia, which was attenuated in uPA −/− and uPAR −/− mice. Administration of aprotinin, a plasmin antagonist, also delayed mortality and attenuated thrombocytopenia. Platelet trapping in cerebral venules or alveolar capillaries was evident in +/+ mice but absent in uPAR −/− mice. In contrast, macrophage sequestration in cerebral venules or alveolar capillaries was evident in both +/+ and uPAR −/− mice. Polymorphonuclear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR −/− mice. These results demonstrate that the uPAR deficiency attenuates the severity of SM, probably by its important role in platelet kinetics and trapping. These results therefore suggest that platelet sequestration contributes to the pathogenesis of SM.

P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines

Publisher: Elsevier BV

Date: 12-2002

DOI: 10.1046/J.1523-1755.2002.T01-1-00651.X

Abstract: Infectious diseases are among the most morbid events in uremia. The uremic toxin p-cresol may play a role in the immunodeficiency of uremia by depressing phagocyte functional capacity. Leukocyte adhesion to endothelium, a key event in the immune response, is mediated by endothelial adhesion molecules. These include intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, which are induced by various inflammatory cytokines. We asked whether p-cresol alters endothelial adhesion molecule expression and modifies endothelial/leukocyte adhesion. Human umbilical vein endothelial cells (HUVEC) were incubated with p-cresol in the presence or absence of tumor necrosis factor (TNF) or interleukin-1beta (IL-1beta). Thereafter, the endothelial molecules ICAM-1, VCAM-1, and E-selectin were quantitated and the monocyte (THP-1) adhesion to HUVEC measured. P-cresol decreased cytokine-induced protein and mRNA expression of ICAM-1 and VCAM-1. In addition, p-cresol significantly decreased the adhesion of THP-1 to cytokine-stimulated HUVEC. P-cresol may play a role in the immune defect of uremic patients by inhibiting cytokine-induced endothelial adhesion molecule expression and endothelium/monocyte adhesion.

Platelets as pathogenetic effectors and killer cells in cerebral malaria

Publisher: Informa UK Limited

Date: 03-05-2016

DOI: 10.1080/17474086.2016.1179571

Infectious Diseases of the Nervous System and Their Impact in Developing Countries

Publisher: Public Library of Science (PLoS)

Date: 27-02-2009

DOI: 10.1371/JOURNAL.PPAT.1000199

The responses of osteoblasts, osteoclasts and endothelial cells to zirconium modified calcium-silicate-based ceramic

Publisher: Elsevier BV

Date: 11-2008

DOI: 10.1016/J.BIOMATERIALS.2008.08.006

Abstract: In this study we have developed Ca(3)ZrSi(2)O(9) (Baghdadite) ceramics by incorporating Zirconium in Ca-Si system and determined their biological properties. Ca(3)ZrSi(2)O(9) ceramics possess apatite-formation ability in simulated body fluid, indicating their potential bioactivity. The response of human osteoblast like cells (HOB), osteoclast and endothelial cells when cultured on Ca(3)ZrSi(2)O(9) ceramics was investigated. Scanning electron microscopy and immunofluorescence studies demonstrated that this material supports HOB cell attachment with organized cytoskeleton structure. Compared to CaSiO(3), Ca(3)ZrSi(2)O(9) ceramics induced increased HOB proliferation and differentiation as shown by increased methyltetrazidium salt (MTS), alkaline phosphatase activity, and mRNA expression levels of bone-related genes (Collagen type I, alkaline phosphatase, Bone Sialoprotein, receptor activator of NF-kappaB ligand and osteoprotegerin). Ca(3)ZrSi(2)O(9) ceramics supported the fusion of monocytes to form functional osteoclasts with their characteristic features of f-actin ring structures and the expression of alpha(v)beta(3) integrin consistent with functional activity. Osteoclasts cultured on Ca(3)ZrSi(2)O(9) expressed increased levels of osteoclast-related genes Cathepsin K, Carbonic Anhydrase II, Matrix metalloproteinase-9, receptor activator of NF-kappaB and Calcitonin Receptor, consistent with the formation of functional osteoclasts. In addition to HOB and osteoclasts, Ca(3)ZrSi(2)O(9) supported the attachment of endothelial cells, which expressed the endothelial cell markers ZO-1 and VE-Cadherin. Results presented here indicate that Ca(3)ZrSi(2)O(9) ceramics have the potential for applications in bone tissue regeneration.

Inhibition of Interleukin 1β Signaling by Anakinra Ameliorates Proinflammatory Cytokine Responses in Zika Virus–Infected Human Blood-Brain Barrier Endothelial Cells

Publisher: Oxford University Press (OUP)

Date: 22-05-2019

DOI: 10.1093/INFDIS/JIZ276

Tumour necrosis factor in neonatal listeriosis: a case report

Publisher: Springer Science and Business Media LLC

Date: 06-1989

DOI: 10.1007/BF00441521

Abstract: Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.

Platelets and microparticles in cerebral malaria: the unusual suspects

Publisher: Elsevier BV

Date: 06-2011

DOI: 10.1016/J.DDMEC.2011.11.004

Strategies for inhibition of tumor necrosis factor in vivo

Publisher: Elsevier BV

Date: 09-1994

DOI: 10.1016/0966-842X(94)90444-8

FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

Publisher: American Chemical Society (ACS)

Date: 25-09-2012

DOI: 10.1021/CN300093G

Effect of polyunsaturated fatty acids (PUFAs) on airway epithelial cells' tight junction

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.PUPT.2016.07.004

Prevention of experimental cerebral malaria by anticytokine antibodies. Interleukin 3 and granulocyte macrophage colony-stimulating factor are intermediates in increased tumor necrosis factor producti

Publisher: Rockefeller University Press

Date: 10-1988

DOI: 10.1084/JEM.168.4.1499

Abstract: IL-3 and granulocyte/macrophage colony stimulating factor (GM-CSF) are two cytokines released by activated T lymphocytes that stimulate the growth and differentiation of various hematopoietic cell lines, among which are macrophages. It has been shown that TNF/cachectin, another cytokine that is released mostly by activated macrophages, plays a central role in experimental cerebral malaria (CM), an acute and lethal neurological syndrome induced by Plasmodium berghei ANKA infection in CBA mice. Since CM requires functional CD4+ T lymphocytes to occur, we explored, by injecting rabbit antibodies to murine rIL-3 and/or GM-CSF, whether these cytokines are intermediates in the marked TNF release leading to CM. Treatment of infected mice with each antibody separately had no protective effect. In contrast, when both anti-rGM-CSF and anti-rIL-3 antibodies were injected together (a) the occurrence of neurological syndrome was prevented in 90% of the cases (b) the rise in serum TNF was prevented and (c) macrophage accumulation in the spleen was significantly reduced. Murine CM appears to involve a cytokine cascade in which IL-3 and GM-CSF lead to the accumulation of TNF-releasing macrophages in vivo.

Light and heavy ion beam analysis of thin biological sections

Publisher: Elsevier BV

Date: 07-2013

DOI: 10.1016/J.NIMB.2012.11.045

Protective effect of natural TNF-binding protein on human TNF-induced toxicity in mice

Publisher: Elsevier BV

Date: 09-1993

DOI: 10.1016/1043-4666(93)90036-5

Abstract: The in vivo protective effect of urinary TNF-binding protein (uTBP) on acute TNF-induced lesions and lethality was assessed in BALB/c mice. Two animal models, the local Shwartzman reaction and galactosamine (GaLN) induced TNF sensitization, were used. In the former, local cutaneous haemorrhagic necrosis induced by 10 micrograms of recombinant human TNF alpha (r-hTNF) was prevented with iv doses of uTPB as low as 1 microgram when administered concomitantly or 10 micrograms when injected intravenously 60 min before or 30 min after the lesion eliciting-dose of r-hTNF. In the latter model, injection of 1 microgram or r-hTNF caused the death of all mice within 36 h. Either 100 or 250 micrograms of uTBP given intravenously simultaneously with r-hTNF/GaLN totally prevented this mortality. In contrast to anti-human TNF monoclonal antibodies, these very same doses of uTBP significantly protected mice even when injected after the lethal r-hTNF dose. These data confirm in relevant in vivo pathological models the TNF inhibiting capacity of the natural soluble TNF receptor I.

The lectin-like domain of tumor necrosis factor-α increases membrane conductance in microvascular endothelial cells and peritoneal macrophages

Publisher: Wiley

Date: 10-1999

DOI: 10.1002/(SICI)1521-4141(199910)29:10<3105::AID-IMMU3105>3.0.CO;2-A

Circulating Red Cell–derived Microparticles in Human Malaria

Publisher: Oxford University Press (OUP)

Date: 03-2011

DOI: 10.1093/INFDIS/JIQ104

Mass cytometry provides unprecedented insight into the role of B cells during the pathogenesis of multiple sclerosis

Publisher: Whitehouse Publishing

Date: 04-2020

DOI: 10.47795/FZHZ8873

Association of polymorphisms in pro and anti-inflammatory cytokines in children with cerebral malaria, non cerebral malaria and coma of other causes

Publisher: Elsevier BV

Date: 10-2002

DOI: 10.1016/S0198-8859(02)00566-9

Direct cell/cell contact with stimulated T lymphocytes induces the expression of cell adhesion molecules and cytokines by human brain microvascular endothelial cells

Publisher: Wiley

Date: 12-1996

DOI: 10.1002/EJI.1830261242

Abstract: Upon inflammation, stimulated, but not resting T lymphocytes cross the blood-brain barrier and migrate into the central nervous system. This study shows that direct contact between stimulated T lymphocytes and human brain microvascular endothelial cells (HB-MVEC) induces phenotypic and functional changes on the latter cells. Plasma membranes isolated from stimulated T lymphocytes (S-PM) up-regulated the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on isolated HB-MVEC. In addition, HB-MVEC activated by S-PM secreted interleukin (IL)-6 and IL-8. The levels of ICAM-1, E-selectin, IL-6, and IL-8 expressed in S-PM-activated HB-MVEC were similar to those observed with 1000 U/ml tumor necrosis factor (TNF). In contrast, VCAM-1 expression was 15% of that induced by TNF. Inhibitors of TNF diminished (< or = 45%), but did not abolish the expression of cell adhesion molecules and IL-6 induced by S-PM, IL-8 production being insignificantly affected (< or = 10%). This suggests that membrane-associated TNF was partially involved in HB-MVEC activation. The present study demonstrates that stimulated T lymphocytes are able to activate HB-MVEC upon direct cell contact. This novel mechanism of inducing the expression of cell adhesion molecules may prompt the initial adhesion of stimulated T lymphocytes to brain endothelium.

Platelets activate a pathogenic response to blood-stage Plasmodium infection but not a protective immune response

Publisher: American Society of Hematology

Date: 23-03-2017

DOI: 10.1182/BLOOD-2016-08-733519

Abstract: Platelets are not killer cells of blood-stage Plasmodium parasites. Platelets are not required to activate the protective immune response to blood-stage Plasmodium infection in mice.

Cerebral Malaria - A Neurovascular Pathology with Many Riddles Still to be Solved

Publisher: Bentham Science Publishers Ltd.

Date: 04-2004

DOI: 10.2174/1567202043480116

Abstract: Cerebral malaria (CM), one of the most common fatal complications of the heterogenous syndrome named severe malaria, is indubitably a post-infectious neurovascular pathology, as evidenced by histopathological analyses. This neurological syndrome is characterised not only by the cytoadherence of Plasmodium falciparum-infected erythrocytes, but also by morphological and functional alterations of brain microvascular endothelial cells subsequent to their interactions with circulating cells, such as platelets, monocytes, lymphocytes, and dendritic cells. During CM, host cells, in particular immune cells, are found recruited and activated at the site of sequestration, where they release various soluble molecules. Among these, cytokines play a major role in CM pathogenesis. Indeed, cerebral complications appear to be due to an imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokines (notably interferon-gamma, tumour necrosis factor, lymphotoxin) and chemokine receptors (notably CCR5) are also responsible for blood-brain barrier alterations and biochemical changes leading to the brain parenchymal lesions that can be observed in CM. In return, glial cells can influence blood-borne elements, and thereby worsen the pathology. Numerous problems remain to be solved, especially the sequence of pathological events, namely the order in which the circulating cells sequester on the endothelial wall. A better understanding of the molecular mechanisms involved in CM pathogenesis is needed if we are capable of preventing cerebral complications and improving the quality of patient management.

Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials

Publisher: American Chemical Society (ACS)

Date: 07-05-2019

DOI: 10.1021/ACS.JMEDCHEM.9B00504

Abstract: A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg

Parasite-Derived Plasma Microparticles Contribute Significantly to Malaria Infection-Induced Inflammation through Potent Macrophage Stimulation

Publisher: Public Library of Science (PLoS)

Date: 29-01-2010

DOI: 10.1371/JOURNAL.PPAT.1000744

Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo.

Publisher: American Society for Clinical Investigation

Date: 05-1994

DOI: 10.1172/JCI117215

Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings

Publisher: American Society of Hematology

Date: 18-02-2010

DOI: 10.1182/BLOOD-2009-07-235150

Abstract: During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adhere via platelet decorated ultra-large VWF strings on activated endothelium. Using an in vitro laminar flow model, we have demonstrated tethering and firm adhesion of IEs to the endothelium specifically at sites of platelet accumulation. We also show that an IE pro-adhesive state, capable of supporting high levels of binding within minutes of induction, can be removed through the action of the VWF protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). We propose that this new mechanism contributes to sequestration both independently of and in concert with current adhesion mechanisms.

Role of TNF in immunopathology of leprosy

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/S0923-2494(93)80083-B

Serum tumour necrosis factor in newborns at risk for infections

Publisher: Springer Science and Business Media LLC

Date: 06-1990

DOI: 10.1007/BF02034754

A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI

Publisher: American Society for Clinical Investigation

Date: 02-2008

DOI: 10.1172/JCI33314

The microcirculation in severe malaria

Publisher: Wiley

Date: 11-10-2004

DOI: 10.1080/10739680490503311

Abstract: Severe malaria in humans and animals is initiated by interactions between malaria-infected cells, host blood cells (including monocytes, T cells and platelets) and endothelial cells of the microcirculation. Adhesion to vascular cells, and possible vascular obstruction in severe human disease, involves interaction between host receptors and parasite-derived proteins, such as the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Our understanding of how different PfEMP1 variants may target infected erythrocytes to specific sites, such as the placenta, is rapidly increasing. However, in most instances downstream immune-mediated inflammatory processes appear more central than parasite accumulation to development of severe malaria. Using genetically-manipulated animal models of severe malaria, key roles for CD8 T cells and mediators such as lymphotoxin in the pathogenesis of murine disease have been established. Experimental and human studies suggest vascular deposition of activated platelets may have a central role. Here, we review some recent advances in the understanding of severe malaria pathogenesis from human and animal studies, focusing on events at the level of the microcirculation, and highlight the role for activated host cells in initiating the pathology of the disease.

Tumor Necrosis Factor-α and Angiostatin Are Mediators of Endothelial Cytotoxicity in Bronchoalveolar Lavages of Patients with Acute Respiratory Distress Syndrome

Publisher: American Thoracic Society

Date: 09-2002

DOI: 10.1164/RCCM.2109004

Abstract: Acute respiratory distress syndrome (ARDS) is characterized by an extensive alveolar capillary leak, permitting contact between intra-alveolar factors and the endothelium. To investigate whether factors contained in the alveolar milieu induce cell death in human lung microvascular endothelial cells, we exposed these cells in vitro to bronchoalveolar lavage fluid (BALF) supernatants from control patients, patients at risk of developing ARDS, and patients with early- and late-phase ARDS. In contrast to BALF from control patients, a significant cytotoxicity was found in BALF from patients at risk of developing ARDS, with late-phase ARDS, and especially from patients with early-phase ARDS. Subsequently, we determined the levels of factors known to exert cytotoxicity in endothelial cells, i.e., tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and angiostatin. BALF from patients at risk of developing ARDS, with early-phase ARDS, and with late-phase ARDS, contained increased levels of TNF-alpha and angiostatin, but not of TGF-beta1, as compared with BALF from control patients. Whereas inhibition of TGF-beta1 had no effect in this setting, neutralization of TNF-alpha or angiostatin inhibited the cytotoxic activity on endothelial cells of part of the early-phase ARDS BALF. These results indicate that TNF-alpha and angiostatin may contribute to ARDS-related endothelial injury.

Pathogenic Role of P-Selectin in Experimental Cerebral Malaria

Publisher: Elsevier BV

Date: 03-2004

DOI: 10.1016/S0002-9440(10)63166-5

Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane‐bound TNF in experimental cerebral malaria

Publisher: Wiley

Date: 07-1997

DOI: 10.1002/EJI.1830270719

Abstract: Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1null) mice, which were as susceptible as wild-type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-gamma was found between infected wild-type and Tnfr1null or Tnfr2null mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1null mice-both of which developed CM-whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2null mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1null or Tnfr2null mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 up-regulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

Pathophysiology of Cerebral Malaria

Publisher: Wiley

Date: 05-2003

DOI: 10.1111/J.1749-6632.2003.TB03135.X

Abstract: Cerebral malaria (CM), one of the most serious complications of Plasmodium falciparum infection, is characterized by the sequestration of infected erythrocytes (IEs) in cerebral microvascular beds. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances, and host immune responses all play a role. Studies in a murine model of CM showed a potential role for host cells, especially platelets, in the pathogenesis of CM. Indeed, urokinase plasminogen activator receptor (uPAR CD87) deficiency attenuates the severity of CM, most likely by its important role in platelet kinetics and trapping. These results led us to evaluate whether platelets have a role in the human disease. By immunostaining of brain s les from Malawian patients, we determined that the surface of platelet accumulation and the proportion of vessels filled with platelets were significantly higher in patients who died of CM than in those who died of other causes. We then investigated the role of platelets in IE cytoadhesion in vitro, using CD36-binding IE (IECD36) and CD36-deficient (CD36DEF) brain microvascular endothelial cells (ECs). Coincubation studies indicated that platelets can induce strong IECD36 binding to CD36DEF ECs and, conversely, can hide constitutively expressed falciparum receptors such as chondroitin sulfate A. Thus, platelets may provide an adhesion receptor to microvascular beds originally devoid of it. This novel mechanism of cytoadhesion may reorient the sequestration of different parasite phenotypes and play an important role in the pathogenesis of severe malaria.

An in vitro blood–brain barrier model: Cocultures between endothelial cells and organotypic brain slice cultures

Publisher: Proceedings of the National Academy of Sciences

Date: 17-02-1998

DOI: 10.1073/PNAS.95.4.1840

Abstract: This communication describes a novel in vitro blood–brain barrier (BBB) model: organotypic slice cultures from the central nervous system were overlaid on endothelial cell monolayers grown on permeable membranes. Morphological, electrophysiological, and microdialysis approaches were carried out to characterize and validate this model. After 10 days in coculture, morphological studies reveal the presence of tight junctions. Electrophysiological recordings of neuronal activity performed on organotypic cultures with or without an endothelial cell monolayer show that litude of evoked responses were comparable, indicating good viability of cocultures after 2 weeks. Perfusion of known BBB permeable or nonpermeable molecules was used to test the coculture tightness in conjunction with electrophysiological or microdialysis approaches: application of glutamate (Glu), which doesn’t easily cross the BBB, triggers off rhythmic activity only in control cultures, whereas epileptogenic activity was observed in both control cultures and cocultures during perfusions with picrotoxin, a molecule that can diffuse through the BBB. Finally, the microdialysis technique was used to determine the permeability of molecules coming from the perfusion chamber: l -dopa, dopamine, and Glu were employed to assess the selective permeability of the coculture model. Thus, these results indicate that the in vitro model described possesses characteristics similar to those of the BBB in situ and that cocultures of organotypic slices and endothelial cell monolayers have potential as a powerful tool for studying biochemical mechanisms regulating BBB function and drug delivery to the central nervous system.

Immunopathological consequences of the loss of engulfment genes: the case of ABCA1

Publisher: EDP Sciences

Date: 2005

DOI: 10.1051/JBIO:2005020

Abstract: Programmed cell death plays a crucial role in the maintenance of cell homeostasis. An initial, effector phase leads to the generation of apoptotic corpses and is closely followed by a swift clearance by professional or amateur phagocytes. Several aspects distinguish this latter process of engulfment of dying cells from the classical forms of phagocytosis. They concern all aspects of the process from the recognition of the prey to the final outcome, i.e. immunological silence. The engulfment of dead cells is a process highly conserved through evolution and it has been studied in parallel in two systems, mammalian cells and the nematode C. elegans. ABCA1 and its ortholog CED-7 in the nematode are key players of engulfment. Their mode of action is somehow original in the panorama of engulfment receptors since they act as lipid transporters. While in the worm the loss of CED-7 has phenotypic consequences exclusively on engulfment, in the mouse the deletion of ABCA1 by homologous recombination has highlighted broad consequences on macrophage biology. Among those we will discuss here the aberrant responses of ABCA1-/- mice to Plasmodium berghei ANKA infection, concerning in particular the development of cerebral malaria (CM), a cytokine-induced immunopathology. This syndrome involves a central role of monocytes and, as shown recently, high levels of circulating microparticles. It was found that ABCA1 loss completely protects against CM and its associated mortality. This observation, together with the demonstration of quantitative and functional modifications of microparticles, suggests that microparticles may be involved in CM pathogenesis. The ABCA1 transporter thus appears to control susceptibility to CM, thereby providing new insights in its pathophysiological mechanisms and potential new therapeutic avenues.

Platelets ReorientPlasmodium falciparum–Infected Erythrocyte Cytoadhesion to Activated Endothelial Cells

Publisher: Oxford University Press (OUP)

Date: 15-01-2004

DOI: 10.1086/380761

Abstract: Severe malaria is characterized by the sequestration of Plasmodium falciparum-infected erythrocytes (IEs). Because platelets can affect tumor necrosis factor (TNF)-activated endothelial cells (ECs), we investigated their role in the sequestration of IEs, using IEs that were selected because they can adhere to endothelial CD36 (IE(CD36)), a P. falciparum receptor that is expressed on platelets. The results of coincubation studies indicated that platelets can induce IE(CD36) binding to CD36-deficient brain microvascular ECs. This induced cytoadhesion resisted physiological shear stress, was increased by EC stimulation with TNF, and was abolished by anti-CD36 monoclonal antibody. Immunofluorescence and scanning electron microscopy results showed that platelets serve as a bridge between IEs and the surface of ECs and may therefore provide receptors for adhesion to microvascular beds that otherwise lack adhesion receptors. This novel mechanism of cytoadhesion may reorient the sequestration of different parasite phenotypes and play an important role in the pathogenesis of severe malaria.

Pathogenesis of Cerebral Malaria: Recent Experimental Data and Possible Applications for Humans

Publisher: American Society for Microbiology

Date: 10-2001

DOI: 10.1128/CMR.14.4.810-820.2001

Abstract: Malaria still is a major public health problem, partly because the pathogenesis of its major complication, cerebral malaria, remains incompletely understood. Experimental models represent useful tools to better understand the mechanisms of this syndrome. Here, data generated by several models are reviewed both in vivo and in vitro we propose that some pathogenic mechanisms, drawn from data obtained from experiments in a mouse model, may be instrumental in humans. In particular, tumor necrosis factor (TNF) receptor 2 is involved in this syndrome, implying that the transmembrane form of TNF may be more important than the soluble form of the cytokine. It has also been shown that in addition to differences in immune responsiveness between genetically resistant and susceptible mice, there are marked differences at the level of the target cell of the lesion, namely, the brain endothelial cell. In murine cerebral malaria, a paradoxical role of platelets has been proposed. Indeed, platelets appear to be pathogenic rather than protective in inflammatory conditions because they can potentiate the deleterious effects of TNF. More recently, it has been shown that interactions among platelets, leukocytes, and endothelial cells have phenotypic and functional consequences for the endothelial cells. A better understanding of these complex interactions leading to vascular injury will help improve the outcome of cerebral malaria.

Role of Granulocyte-Macrophage Colony-Stimulating Factor in Pulmonary Fibrosis Induced in Mice by Bleomycin

Publisher: Informa UK Limited

Date: 1993

DOI: 10.3109/01902149309031729

Abstract: The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in pulmonary fibrosis elicited in mice by the intratracheal instillation of bleomycin was investigated by (1) evaluation of GM-CSF mRNA levels, (2) administration of GM-CSF, and (3) administration of anti-GM-CSF antibody. A significant increase of the GM-CSF mRNA level was evident in the lung RNA on day 5 after bleomycin instillation, but not on day 15. Abdominal infusion of GM-CSF (0.5 micrograms/h during days 7-15) did prevent the collagen deposition induced by bleomycin, as measured by the lung hydroxyproline content on day 15. In contrast, anti-GM-CSF antibody markedly aggravated the collagen deposition. On histological sections the proportion of lungs showing fibrosing alveolitis was decreased by GM-CSF and increased by anti-GM-CSF IgG. The percentage and number of macrophages within the bronchoalveolar lavage (BAL) fluid was increased by GM-CSF infusion and decreased by anti-GM-CSF antibodies. This study demonstrates that pulmonary GM-CSF has an inhibitory influence upon the alveolar remodeling and collagen deposition associated with pulmonary fibrosis.

Administration of recombinant interleukin 2 to mice enhances production of hemopoietic and natural killer cells

Publisher: Wiley

Date: 1986

DOI: 10.1002/EJI.1830161012

Abstract: Seven days of continuous perfusion of mice with human recombinant interleukin 2 (rIL 2) (approximately 3 X 10(4) U/day) increased the percentage of large mononuclear leukocytes (LML) among bone marrow, spleen, lymph node cells and liver interstitial cells (LIC). An increase in the lymphokine-activated killer (LAK) activity was evident in these organs. The greatest increase in the number of LML and in the LAK activity was observed among the liver interstitial cells (about 500-fold increase). The LML were nonphagocytic, Thy-1+, sIg-, Ly 2+, L3T4- and asialo Gm1+. Perfusion of athymic nude mice, or of thymectomized, irradiated radiation chimera, showed that the Thy-1+, LAK+ LML were the thymus and T lymphocyte-independent progeny of Thy-1- marrow precursors. The LML had no T cell function in a graft-vs.-host reactivity assay, neither did they have an inhibitory effect on T lymphocyte function in vivo. rIL 2 perfusion did not significantly affect the medullary hemopoiesis but did strongly enhance the extramedullary hemopoiesis, particularly within the interstice of the liver: the number of erythroid and myeloid cell was increased as well as the number of colony-forming units per spleen and colony-forming units per culture for various lineages (20-50-fold increment). These results show that in vivo, rIL 2 has a global enhancing effect on hemopoiesis together with a more selective influence on the production of LML.

Cerebral malaria: Mediators, mechanical obstruction or more?

Publisher: Elsevier BV

Date: 1994

DOI: 10.1016/0169-4758(94)90236-4

Pathogenetic Immune Responses in Cerebral Malaria

Publisher: Springer International Publishing

Date: 2017

DOI: 10.1007/978-3-319-45210-4_4

Citicoline (CDP-choline): What role in the treatment of complications of infectious diseases

Publisher: Elsevier BV

Date: 07-2009

DOI: 10.1016/J.BIOCEL.2009.02.011

Abstract: A dysregulated host immune response, as opposed to the intrinsic virulence of a microbial pathogen induces a large part of the pathology seen in infectious diseases. However, current therapies are designed to target the pathogen rather than the underlying pathogenic mechanisms responsible for the manifestation of the pathology. Recent studies have highlighted the role of endothelial cell alteration in the pathology induced in sepsis and cerebral malaria. The endothelial onslaught described, is similar to that seen during ischemia reperfusion in stroke. Protecting endothelial cell membranes during sepsis and cerebral malaria, using citicoline in the same way as in stroke, has thus emerged as a new strategy that needs to be evaluated urgently. Citicoline is a natural compound that is registered for use in ischemic stroke, head trauma and neurological disorders. It enters the phosphatidylcholine synthesis pathway as a rate-limiting step and is involved in the modulation of a large number of metabolic pathways and neurotransmitter levels, and also in the biosynthesis of phospholipids in neuronal membranes. This short review highlights the potential role of citicoline as part of adjunct therapy in the treatment of infectious diseases.

Induction of acute thrombocytopenia and infection of megakaryocytes by Rauscher murine leukemia virus reflect the genetic susceptibility to leukemogenesis.

Publisher: Rockefeller University Press

Date: 03-1983

DOI: 10.1084/JEM.157.3.1028

Abstract: Acute thrombocytopenia and megakaryocyte infection have been investigated during the preleukemic phase of the disease induced by the Rauscher murine leukemia virus (RMuLV) in mice. Injection of RMuLV, either intravenously or intraperitoneally, rapidly induced thrombocytopenia, possibly as a result of direct interaction between platelets and viral particles. The susceptibility to this acute thrombocytopenia was genetically controlled and was inherited as a dominant trait. Murine strains with H-2d or H-2k haplotype, which are susceptible to the induction of leukemia by RMuLV, developed thrombocytopenia, whereas leukemia-resistant H-2b and H-2q strains of mice failed to develop thrombocytopenia. Using B10 H-2-congenic and intra-H-2-recombinant mice, it was shown that the susceptibility to RMuLV-induced thrombocytopenia was controlled by gene(s) in or closely linked to the D region of the H-2 complex. Megakaryocytes may be one of the first sites for the replication of RMuLV. Indeed, among bone marrow cells, only megakaryocytes expressed viral antigens gp70 and p30 during the initial phase of RMuLV infection. In addition, megakaryocytes from infected mice were able to transfer preleukemic thrombocytopenia as well as leukemia in syngeneic mice. The infection of megakaryocytes by RMuLV appears to be genetically controlled in a manner similar to the induction of thrombocytopenia, since only the megakaryocytes from mice developing thrombocytopenia were infected by RMuLV. These results indicate that the gene(s) governing the induction of thrombocytopenia by RMuLV may be the same gene(s) (or closely linked to the gene) that controls the susceptibility to leukemogenesis, and would be consistent with the expression of the gene product, presumably a receptor-like molecule for RMuLV, on platelet and megakaryocyte membranes.

Cerebral malaria: Which parasite? Which model?

Publisher: Elsevier BV

Date: 06-2005

DOI: 10.1016/J.DDMOD.2005.05.015

Cerebral malaria pathogenesis: revisiting parasite and host contributions

Publisher: Future Medicine Ltd

Date: 02-2012

DOI: 10.2217/FMB.11.155

Abstract: Cerebral malaria is one of a number of clinical syndromes associated with infection by human malaria parasites of the genus Plasmodium. The etiology of cerebral malaria derives from sequestration of parasitized red cells in brain microvasculature and is thought to be enhanced by the proinflammatory status of the host and virulence characteristics of the infecting parasite variant. In this article we examine the range of factors thought to influence the development of Plasmodium falciparum cerebral malaria in humans and review the evidence to support their role.

Association between protective efficacy of anti-lipopolysaccharide (LPS) antibodies and suppression of LPS-induced tumor necrosis factor alpha and interleukin 6. Comparison of O side chain-specific an

Publisher: Rockefeller University Press

Date: 03-1990

DOI: 10.1084/JEM.171.3.889

Abstract: Two-core LPS antibodies, the rabbit J5 polyclonal antiserum and the human anti-lipid A IgM mAb HA-1A, did not improve the survival of mice challenged with E. coli O111 or P. aeruginosa 3, or with the LPS extracted from them, and did not decrease the incidence of Shwartzman reactions in rabbits challenged with O111 LPS. In contrast, O side chain-specific rabbit antisera were protective in these models. The protection afforded by O side chain-specific antisera against endotoxin lethality was associated with decreased LPS-induced serum TNF and IL-6 levels, whereas core LPS antibodies had no effect on TNF or IL-6 levels. The absence of reduction of LPS-induced cytokines levels by core LPS antibodies suggests that these antibodies are not able to prevent the interactions between LPS and target cells.

Platelet-endothelial cell interactions in cerebral malaria: The end of a cordial understanding

Publisher: Georg Thieme Verlag KG

Date: 2009

DOI: 10.1160/TH09-05-0337

Abstract: Cerebral malaria is an acute encephalopathy evolving from an infection with Plasmodium falciparum which kills more than one million people each year. Brain tissues from patients who died with cerebral malaria revealed multifocal capillary obstruction by parasitised red blood cells, platelets, and leukocytes. Many studies are unified in their proposal of two major hypotheses consisting of cell adhesion to the brain endothelium and excessive immune stimulation resulting in further vascular inflammation, prothrombotic cell activation, mechanical obstruction of cerebral capillaries and, consequently, blood-brain barrier disruption. Platelets and endothelial cells communicate on multiple levels. Infection-induced changes in platelets and endothelial cells occur in cerebral malaria, resulting in their concomitant activation, increased interactions between these two cell types, and a secondary procoagulant or hypercoagulable state. Here we review evidence for these mechanisms and highlight the possible role of platelets as effectors of endothelial damage in cerebral malaria. A better understanding of the complex regulation of these various interactions between brain endothelial cells and platelets in the context of cerebral malaria may prove useful in the development of new approaches to the treatment of this disease.

Cryptococcal transmigration across a model brain blood-barrier: evidence of the Trojan horse mechanism and differences between Cryptococcus neoformans var. grubii strain H99 and Cryptococcus gattii strain R265

Publisher: Elsevier BV

Date: 2016

DOI: 10.1016/J.MICINF.2015.08.017

Abstract: Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg) cause neurological disease and cross the BBB as free cells or in mononuclear phagocytes via the Trojan horse mechanism, although evidence for the latter is indirect. There is emerging evidence that Cn and the North American outbreak Cg strain (R265) more commonly cause neurological and lung disease, respectively. We have employed a widely validated in vitro model of the BBB, which utilizes the hCMEC/D3 cell line derived from human brain endothelial cells (HBEC) and the human macrophage-like cell line, THP-1, to investigate whether transport of dual fluorescence-labelled Cn and Cg across the BBB occurs within macrophages. We showed that phagocytosis of Cn by non-interferon (IFN)-γ stimulated THP-1 cells was higher than that of Cg. Although Cn and Cg-loaded THP-1 bound similarly to TNF-activated HBECs under shear stress, more Cn-loaded macrophages were transported across an intact HBEC monolayer, consistent with the predilection of Cn for CNS infection. Furthermore, Cn exhibited a higher rate of expulsion from transmigrated THP-1 compared with Cg. Our results therefore provide further evidence for transmigration of both Cn and Cg via the Trojan horse mechanism and a potential explanation for the predilection of Cn to cause CNS infection.

Vascular endothelial cells cultured from patients with cerebral or uncomplicated malaria exhibit differential reactivity to TNF

Publisher: Hindawi Limited

Date: 07-10-2010

DOI: 10.1111/J.1462-5822.2010.01528.X

Significance of cytokine production and adhesion molecules in malarial immunopathology

Publisher: Elsevier BV

Date: 08-1990

DOI: 10.1016/0165-2478(90)90113-5

Abstract: The pathological expression in malaria infection depends largely on immunopathologic responses induced by the parasite. In the past few years, we have attempted to analyze mechanisms by which inappropriate immune response to some malarial antigens can generate major complications of malaria and particularly neurovascular lesions. To this end, we have undertaken a study aimed at a more precise definition of immunopathological parameters of malaria infection, and more particularly those involved in cerebral malaria (CM). CM, the most severe complication of falciparum infection in man, represents a major problem of public health at the world level.

Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

Publisher: Springer Science and Business Media LLC

Date: 12-2007

DOI: 10.1186/1471-2164-8-452

Abstract: Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R) and CM-susceptible (CM-S) mice, upon infection by Plasmodium berghei ANKA (PbA). We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c), and in CM-S (CBA/J and C57BL/6) mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

Modulation of soluble and membrane-bound TNF-induced phenotypic and functional changes of human brain microvascular endothelial cells by recombinant TNF binding protein I

Publisher: Elsevier BV

Date: 07-1997

DOI: 10.1016/S0165-5728(97)00067-2

Abstract: In this study, the effects of TNF binding protein I (TBP I) on TNF-induced changes of human brain microvascular endothelial cells (MVEC) were investigated. TBP I completely abolished TNF-induced IL-6 production and E-selectin induction, while it partially inhibited TNF-induced IL-8 production and up-regulation of ICAM-1 and VCAM-1. Moreover, TBP I significantly inhibited TNF-induced cytotoxicity and leukocyte adherence on human brain MVEC. The inhibitory activity of TBP I for TNF was dose-dependent and related to the time of administration after TNF stimulation. In addition, TBP I inhibited membrane-bound TNF induced activation of human brain MVEC, but the concentration required was about 10-fold higher than that for soluble TNF. These results indicate a therapeutic potential for TBP I in diseases of the central nervous system associated with TNF overproduction.

The Brain Microvascular Endothelium Supports T Cell Proliferation and Has Potential for Alloantigen Presentation

Publisher: Public Library of Science (PLoS)

Date: 08-01-2013

DOI: 10.1371/JOURNAL.PONE.0052586

Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium

Publisher: Wiley

Date: 17-06-2009

DOI: 10.1096/FJ.09-135822

Abstract: Cerebral malaria (CM) is characterized by accumulation of circulating cells within brain microvessels, among which platelets play an important role. In vitro, platelets modulate the cytoadherence of Plasmodium falciparum-parasitized red blood cells (PRBCs) to brain endothelial cells. Here we show for the first time that platelet microparticles (PMPs) are able to bind to PRBCs, thereby transferring platelet antigens to the PRBC surface. This binding is largely specific to PRBCs, because PMPs show little adherence to normal red blood cells. PMP adherence is also dependent on the P. falciparum erythrocyte membrane protein 1 variant expressed by PRBCs. PMP binding to PRBCs decreases after neutralization of PRBC surface proteins by trypsin or after treatment of PMPs with a mAb to platelet-endothelial cell adhesion molecule-1 (CD31) and glycoprotein IV (CD36). Furthermore, PMP uptake is a dynamic process that can be achieved by human brain endothelial cells (HBECs), inducing changes in the endothelial phenotype. Lastly, PMPs dramatically increase PRBC cytoadherence to HBECs. In conclusion, our study identifies several mechanisms by which PMPs may participate in CM pathogenesis while interacting with both PRBCs and HBECs. PMPs thereby provide a novel target for antagonizing interactions between vascular cells that promote microvascular sludging and blood brain barrier alteration during CM.

TNF inhibition and sepsis — sounding a cautionary note

Publisher: Springer Science and Business Media LLC

Date: 11-1997

DOI: 10.1038/NM1197-1193

Investigation of the mouse cerebellum using STIM and μ-PIXE spectrometric and FTIR spectroscopic mapping and imaging

Publisher: Elsevier BV

Date: 10-2011

DOI: 10.1016/J.NIMB.2011.02.034

Abnormal blood vessels formed by human liver cavernous hemangioma endothelial cells in nude mice are suitable for drug evaluation

Publisher: Elsevier BV

Date: 12-2009

DOI: 10.1016/J.MVR.2009.08.007

Abstract: Cavernous hemangioma is vascular malformation with developmental aberrations. It was assumed that the abnormality of endothelial cells contributed greatly to the occurrence of cavernous hemangioma. In our previous study, we have found distinct characteristics of endothelial cells derived from human liver cavernous hemangioma (HCHEC). Here, we reported the abnormal vascular vessels formed by primary HCHEC in nude mice and that the drug podophyllotoxin can destroy HCHEC in vitro and in vivo. HCHEC was isolated from a human liver cavernous hemangioma specimen, and the HCHEC generated a red hemangioma-like mass 7 days after subcutaneously co-inoculating HCHEC and human liver cancer cells (Bel-7402) in nude mice. Lentiviral expression of GFP and immunohistochemistry for human CD31 was used to confirm that the HCHEC formed the blood vessels in nude mice. And the pathological features of vascular vessels formed by HCHEC were very similar to clinical cavernous hemangioma. In addition, by MTT assay, the drug podophyllotoxin was found inhibiting HCHEC viability, and by TUNEL and DNA ladder assays, podophyllotoxin was found inducing apoptosis of HCHEC. Moreover, podophyllotoxin was also effective for destroying the abnormal vascular vessels in the hemangioma-like mass in nude mice. In summary, the HCHEC can form abnormal blood vessels in nude mice, and we can evaluate drugs for cavernous hemangioma by using HCHEC in vitro and in vivo.

Circulating Endothelial Microparticles in Malawian Children With Severe Falciparum Malaria Complicated With ComaRESEARCH LETTERS

Publisher: American Medical Association (AMA)

Date: 02-06-2004

DOI: 10.1001/JAMA.291.21.2542-B

Perillyl alcohol modulates activation, permeability and integrity of human brain endothelial cells induced by Plasmodium falciparum

Publisher: FapUNIFESP (SciELO)

Date: 2023

DOI: 10.1590/0074-02760230033

A murine model of infection with Rickettsia prowazekii: implications for pathogenesis of epidemic typhus

Publisher: Elsevier BV

Date: 06-2007

DOI: 10.1016/J.MICINF.2007.03.008

Abstract: Epidemic typhus remains a major disease threat, furthermore, its etiologic agent, Rickettsia prowazekii, is classified as a bioterrorism agent. We describe here a murine model of epidemic typhus that reproduced some features of the human disease. When BALB/c mice were inoculated intravenously with R. prowazekii (Breinl strain), they survived but did not clear R. prowazekii infection. Immunohistological analysis of tissues and quantitative PCR showed that R. prowazekii was present in blood, liver, lungs and brain 1 day after infection and persisted for at least 9 days. Importantly, infected mice developed interstitial pneumonia, with consolidation of the alveoli, hemorrhages in lungs, multifocal granulomas in liver, and hemorrhages in brain, as seen in humans. Circulating antibodies directed against R. prowazekii were detected at day 4 post-infection and steadily increased for up to 21 days, demonstrating that R. prowazekii lesions were independent of humoral immune response. R. prowazekii-induced lesions were associated with inflammatory response, as demonstrated by elevated levels of inflammatory cytokines including interferon-gamma, tumor necrosis factor and the CC chemokine RANTES in the lesions. We concluded that the BALB/c mouse strain provides a useful model for studying the pathogenic mechanisms of epidemic typhus and its control by the immune system.

Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis.

Publisher: Rockefeller University Press

Date: 09-1989

DOI: 10.1084/JEM.170.3.655

Abstract: The role of TNF-alpha/cachectin in the pneumopathy elicited by bleomycin has been investigated. After a single intratracheal bleomycin instillation, an increase of the lung TNF-alpha mRNA level was evident, from days 5 to 15, as shown by Northern gel analysis of whole lung RNA. In contrast, lung IL-1-alpha and GM-CSF mRNA were not detectable. In mice passively immunized with rabbit anti-mouse TNF-alpha IgG, the bleomycin-induced collagen deposition, evaluated by the total lung hydroxyproline assay on day 15, was prevented. Depletion of the CD4 and CD8 T lymphocytes by an in vivo treatment with mAb prevented the bleomycin-induced increase of TNF mRNA level and fibrosis. After an administration of bleomycin in continuous intraperitoneal perfusion, the diffuse alveolar damage observed by light and electron microscopy was almost completely prevented by anti-TNF antibody. These results indicate that in response to bleomycin, the T lymphocytes induce, by an undefined mechanism, an increase of the pulmonary TNF production, which leads to alveolar damage, growth of fibroblast, and collagen deposition.

Dysbiotic Gut Microbiota-Derived Metabolites and Their Role in Non-Communicable Diseases

Publisher: MDPI AG

Date: 17-10-2023

DOI: 10.3390/IJMS242015256

Inhibition of leukocyte adherence and transendothelial migration in cultured human liver vascular endothelial cells by prostaglandin E1

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-1998

DOI: 10.1002/HEP.510270326

Abstract: Primary graft dysfunction is a major complication of orthotopic liver transplantation, and hepatic ischemic reperfusion injury is considered to be its major determinant cause. Although oxygen free radicals play an important role, leukocytes, cytokines, and adhesion molecules also contribute to hepatic ischemic reperfusion injury. Prostaglandin E1 (PGE1) has been shown to protect against impairment and dysfunction of transplanted livers in various experimental models as well as in clinical liver transplantation. In this study, the role of PGE1 on leukocyte adherence and transendothelial migration was investigated in cultured human liver vascular endothelial cells (HLVEC). Our results indicated that stimulated, but not resting, leukocytes exhibited high adhesion and transmigration capacity. HLVEC incubated with tumor necrosis factor (TNF) promoted leukocyte adherence and transendothelial migration. PGE1 inhibited leukocyte adherence to HLVEC when it was preincubated with either HLVEC or leukocytes. Moreover, PGE1 also suppressed stimulated leukocyte transendothelial migration in a dose-dependent manner. The inhibitory activity of PGE1 was further investigated on both HLVEC and leukocytes with attention to adhesion molecules. On HLVEC, PGE1 down-regulated TNF-induced expression of endothelial cell leukocyte adhesion molecule 1 and vascular adhesion molecule 1, but not intercellular adhesion molecule 1. On leukocytes, PGE1 inhibited expression of CD11a/CD18 and membrane-bound TNF on PHA-stimulated leukocytes. PGE1 also suppressed TNF release from the stimulated leukocytes. These results indicated that inhibition of leukocyte adherence and transendothelial migration is one of the mechanisms by which PGE1 protects liver grafts.

Expression of VEGF 111 and other VEGF-A variants in the rat uterus is correlated with stage of pregnancy

Publisher: Springer Science and Business Media LLC

Date: 08-10-2016

DOI: 10.1007/S00360-016-1040-Y

Abstract: Vascular endothelial growth factor A is a major mediator of angiogenesis, a critically important process in vertebrate growth and development as well as pregnancy. Here we report for the first time the expression of a rare and unusually potent splice variant, VEGF

Toxoplasmic encephalitis

Publisher: Elsevier BV

Date: 11-1992

DOI: 10.1016/0169-4758(92)90170-7

Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the wild-type molecule

Publisher: Wiley

Date: 2001

DOI: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1090>3.0.CO;2-Y

Abstract: In this study, we characterised the anti-tumour as well as the pro-metastatic activities of TNF mutants deficient in their lectin-like activity.1619 We report that, despite reduced systemic toxicity as compared to wild-type (wt) mTNF, a (T104A) and a (T104A-E106A-E109A) mTNF mutant (triple mTNF) retained most of their necrotic and tumouristatic activities, as measured in a CFS-1 fibrosarcoma and a B16BL6 melanoma tumour model, respectively. These mutants also conserved their anti-angiogenic activity, as measured in an in vitro endothelial morphogenesis assay.26 In contrast, the pro-metastatic activity of the T104A and the triple mTNF mutants in the CFS-1 fibrosarcoma and the 3LL-R Lewis lung carcinoma tumour model was significantly lower than that of the wt molecule. These results thus indicate that the lectin-like domain of TNF is not implicated in its necrotic, tumouristatic and anti-angiogenic activities, but that it can contribute to the pro-metastatic effect of the cytokine. In conclusion, in view of their reduced systemic toxicity and pro-metastatic capacity, but their retained anti-tumour activities, lectin-deficient TNF mutants might prove to be therapeutically interesting alternatives to wt TNF.

In the Eye of Experimental Cerebral Malaria

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.AJPATH.2011.05.044

Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells

Publisher: Springer Science and Business Media LLC

Date: 16-04-2009

DOI: 10.1038/LEU.2009.76

Abstract: Multidrug resistance (MDR), a significant impediment to the successful treatment of cancer clinically, has been attributed to the overexpression of P-glycoprotein (P-gp), a plasma membrane multidrug efflux transporter. P-gp maintains sublethal intracellular drug concentrations by virtue of its drug efflux capacity. The cellular regulation of P-gp expression is currently known to occur at either pre- or post-transcriptional levels. In this study, we identify a 'non-genetic' mechanism whereby microparticles (MPs) serve as vectors in the acquisition and spread of MDR. MPs isolated from drug-resistant cancer cells (VLB(100)) were co-cultured with drug sensitive cells (CCRF-CEM) over a 4 h period to allow for MP binding and P-gp transfer. Presence of P-gp on MPs was established using flow cytometry (FCM) and western blotting. Whole-cell drug accumulation assays using rhodamine 123 and daunorubicin (DNR) were carried out to validate the transfer of functional P-gp after co-culture. We establish that MPs shed in vitro from drug-resistant cancer cells incorporate cell surface P-gp from their donor cells, effectively bind to drug-sensitive recipient cells and transfer functional P-gp to the latter. These findings serve to substantially advance our understanding of the molecular basis for the emergence of MDR in cancer clinically and lead to new treatment strategies which target and inhibit MP mediated transfer of P-gp during the course of treatment.

Investigation of Plasma-Derived Lipidome Profiles in Experimental Cerebral Malaria in a Mouse Model Study

Publisher: MDPI AG

Date: 28-12-2022

DOI: 10.3390/IJMS24010501

Abstract: Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children, especially under the age of five, in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms. Increased release of circulating miRNA, proteins, lipids and extracellular vesicles has been found in CM patients and experimental mouse models. We compared lipid profiles derived from the plasma of CBA mice infected with Plasmodium berghei ANKA (PbA), which causes CM, to those from Plasmodium yoelii (Py), which does not. We previously showed that platelet-free plasma (18k fractions enriched from plasma) contains a high number of extracellular vesicles (EVs). Here, we found that this fraction produced at the time of CM differed dramatically from those of non-CM mice, despite identical levels of parasitaemia. Using high-resolution liquid chromatography–mass spectrometry (LCMS), we identified over 300 lipid species within 12 lipid classes. We identified 45 and 75 lipid species, mostly including glycerolipids and phospholipids, with significantly altered concentrations in PbA-infected mice compared to Py-infected and uninfected mice, respectively. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to Py infection and controls. These results suggest that experimental CM could be characterised by specific changes in the lipid composition of the 18k fraction containing circulating EVs and can be considered an appropriate model to study the role of lipids in the pathophysiology of CM.

Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis

Publisher: Public Library of Science (PLoS)

Date: 17-07-2014

DOI: 10.1371/JOURNAL.PPAT.1004236

Morphologic, Phenotypic and Functional Characteristics of Endothelial Cells Derived from Human Hepatic Cavernous Hemangioma

Publisher: S. Karger AG

Date: 2006

DOI: 10.1159/000095965

Abstract: i Backgrounds/Aims: /i The pathogenesis of cavernous hemangiomas is largely unknown, and it is speculated that abnormal vasculogenesis and angiogenesis may be involved. In this study, the characteristics of cavernous hemangioma endothelial cells (CHECs) derived from the human liver were analyzed in terms of morphology, phenotype and function and compared with human liver sinusoidal endothelial cells (LSECs). i Methods and Results: /i By transmission electron microscopy, abnormally expanded endoplasmic reticulum (ER) and similarly arranged cytoplasmic vacuoles were only found in CHECs. Phenotypic analysis showed that the expression of αvβ3 was significantly increased in CHECs. mRNA expression of vascular endothelial growth factor A, and angiopoietins 1 and 2 was significantly increased in CHECs compared to LSECs. The functional analysis indicated that CHECs released more vascular endothelial growth factor A, produced significantly more pro-matrix metalloproteinase 2 (pro-MMP2) and activated MMP2, and exhibited higher procoagulant and fibrinolytic activities compared with LSECs. Confocal microscopy revealed that MMP2 was concentrated in some cytoplasmic granules of CHECs and was consistent with the distribution of expanded ER. CHECs exhibited more activated angiogenesis capacity and formed abnormal capillary-like structures in vitro. i Conclusion: /i These results suggested that endothelial cells (ECs) derived from human cavernous hemangiomas differ from normal ECs in morphology, phenotype and function.

Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential

Publisher: MDPI AG

Date: 18-04-2023

DOI: 10.3390/CANCERS15082364

Abstract: Pleural mesothelioma, previously known as malignant pleural mesothelioma, is an aggressive and fatal cancer of the pleura, with one of the poorest survival rates. Pleural mesothelioma is in urgent clinical need for biomarkers to aid early diagnosis, improve prognostication, and stratify patients for treatment. Extracellular vesicles (EVs) have great potential as biomarkers however, there are limited studies to date on their role in pleural mesothelioma. We conducted a comprehensive proteomic analysis on different EV populations derived from five pleural mesothelioma cell lines and an immortalized control cell line. We characterized three subtypes of EVs (10 K, 18 K, and 100 K), and identified a total of 4054 unique proteins. Major differences were found in the cargo between the three EV subtypes. We show that 10 K EVs were enriched in mitochondrial components and metabolic processes, while 18 K and 100 K EVs were enriched in endoplasmic reticulum stress. We found 46 new cancer-associated proteins for pleural mesothelioma, and the presence of mesothelin and PD-L1/PD-L2 enriched in 100 K and 10 K EV, respectively. We demonstrate that different EV populations derived from pleural mesothelioma cells have unique cancer-specific proteomes and carry oncogenic cargo, which could offer a novel means to extract biomarkers of interest for pleural mesothelioma from liquid biopsies.

Septic Shock due to Cytomegalovirus Infection in Acute Respiratory Distress Syndrome after Falciparum Malaria

Publisher: Oxford University Press (OUP)

Date: 09-1997

DOI: 10.1111/J.1708-8305.1997.TB00804.X

Abstract: Incidence of falciparum malaria in developed countries has increased in recent years due to tourism to tropical countries and immigration from Asia and Africa. In Switzerland, about 250 cases of malaria were reported in 1994 to the Federal Office of Health, including three cases with fatal outcome.1 The most commonly described complications of plasmodia infection are cerebral malaria, acute renal failure, and severe anemia with disseminated intravascular coagulation. However, pulmonary involvement occurs in 3 to 10% of cases and represents the most serious complication of this infection, with a lethality of 70%.2,3 Furthermore, a pronounced general immunosuppression has been reported in malaria patients, which may predispose them to opportunistic infections.4 We report a case of Plasmodium falciparum infection complicated by severe acute respiratory distress syndrome (ARDS) with development of systemic cytomegalovirus (CMV) infection leading to death. This evolution implies a severe immune deficiency associated with malaria, as previously suggested in the literature.

Severe malaria: what’s new on the pathogenesis front?

Publisher: Elsevier BV

Date: 02-2017

DOI: 10.1016/J.IJPARA.2016.08.002

Platelets Potentiate Brain Endothelial Alterations Induced byPlasmodium falciparum

Publisher: American Society for Microbiology

Date: 2006

DOI: 10.1128/IAI.74.1.645-653.2006

Abstract: Brain lesions of cerebral malaria (CM) are characterized by a sequestration of Plasmodium falciparum -parasitized red blood cells (PRBC) and platelets within brain microvessels, as well as by blood-brain barrier (BBB) disruption. In the present study, we evaluated the possibility that PRBC and platelets induce functional alterations in brain endothelium. In a human brain endothelial cell line, named HBEC-5i, exhibiting most of the features demanded for a pathophysiological study of BBB, tumor necrosis factor (TNF) or lymphotoxin α (LT-α) reduced transendothelial electrical resistance (TEER), enhanced the permeability to 70-kDa dextran, and increased the release of microparticles, a recently described indicator of disease severity in CM patients. In vitro cocultures showed that platelets or PRBC can have a direct cytotoxic effect on activated, but not on resting, HBEC-5i cells. Platelet binding was required, as platelet supernatant had no effect. Furthermore, platelets potentiated the cytotoxicity of PRBC for TNF- or LT-α-activated HBEC-5i cells when they were added prior to these cells on the endothelial monolayers. This effect was not observed when platelets were added after PRBC. Both permeability and TEER were strongly affected, and the apoptosis rate of HBEC-5i cells was dramatically increased. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM.

Respective role of TNF receptors in the development of experimental cerebral malaria

Publisher: Elsevier BV

Date: 02-1997

DOI: 10.1016/S0165-5728(96)00185-3

Abstract: The respective role of the two receptors of TNF in experimental cerebral malaria (CM) was investigated. During CM, a significant upregulation of TNF-receptor 2 (TNFR2), but not of TNFR1, was found in brain microvessels of susceptible, but not resistant mice. Mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from CM, while TNFR1-deficient (Tfnr1null) mice were as susceptible as wild-type mice. The protection of Tnfr2null mice could be explained by their absence of ICAM-1 upregulation and leukocyte sequestration, known to occur in brain microvessels of CM-susceptible animals.

In vitro culture of Plasmodium berghei-ANKA maintains infectivity of mouse erythrocytes inducing cerebral malaria

Publisher: Springer Science and Business Media LLC

Date: 25-11-2011

DOI: 10.1186/1475-2875-10-346

Cellular communication via microparticles: role in transfer of multidrug resistance in cancer

Publisher: Future Medicine Ltd

Date: 03-2014

DOI: 10.2217/FON.13.230

Abstract: ABSTRACT: Multidrug resistance (MDR) continues to be a major impediment to the successful treatment of cancer. The two efflux transporters, P-glycoprotein (P-gp) and MRP1 are major contributors to cancer MDR clinically. The upregulation of P-gp leading to MDR was initially understood to occur via pre- and post-transcriptional mechanisms only. However, we demonstrated that microparticles mediate the intercellular exchange and trafficking of bioactive material, including functional P-gp and selected modulatory miRNAs. This exchange of P-gp leads to the dissemination of MDR within a cancer cell population. These findings have significant implications in understanding the cellular basis governing the intercellular acquisition of deleterious traits in cancers, serving to substantially advance our understanding of the molecular basis of the emergence of MDR in cancer clinically.

Magnetic Resonance Spectroscopy Reveals an Impaired Brain Metabolic Profile in Mice Resistant to Cerebral Malaria Infected with Plasmodium berghei ANKA

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1074/JBC.M608035200

Elevated Cell-Specific Microparticles Are a Biological Marker for Cerebral Dysfunctions in Human Severe Malaria

Publisher: Public Library of Science (PLoS)

Date: 14-10-2010

DOI: 10.1371/JOURNAL.PONE.0013415

Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients

Publisher: Wiley

Date: 02-1997

DOI: 10.1002/(SICI)1096-9071(199702)51:2<132::AID-JMV8>3.0.CO;2-8

Abstract: Silicon is considered as the most promising candidate for anodes of next generation lithium-ion batteries owing to its natural abundance and low Li-uptake potential. Building a macroporous structure would alleviate the volume variation and particle fracture of silicon anodes during cycling. However, the common approaches to fabricate macroporous silicon are complex, costly, and high energy-consuming. Herein, bamboo leaves are used as a sustainable and abundant resource to produce macroporous silicon via a scalable magnesiothermic reduction method. The obtained silicon inherits the natural interconnected network from the BLs and the mesopores from the BL-derived silica are engineered into macropores by selective etching after magnesiothermic reduction. These unique structural advantages lead to superior electrochemical performance with efficient electron/ion transport and cycling stability. The macroporous Si@C composite anodes deliver a high capacity of 1,247.7 mAh g

Thrombocytopenia associated with the induction of neonatal tolerance to alloantigens: Immunopathogenic mechanisms

Publisher: Wiley

Date: 09-1989

DOI: 10.1002/EJI.1830190925

Abstract: BALB/c mice rendered tolerant to alloantigens by neonatal injection of semi-allogeneic (C57BL/6 x BALB/c)F1 spleen cells develop a thrombocytopenia in association with an autoimmune lupus-like syndrome. The possible mechanisms involved in the thrombocytopenia were investigated. The development of thrombocytopenia was first detected at 3 weeks of age coinciding with the start of the other autoimmune manifestations and was always related to a state of tolerance and B cell chimerism. There was a significant increase of megakaryocytes in bone marrow and spleens from thrombocytopenic tolerant mice and radiolabeled platelets from these mice were more rapidly eliminated from the bloodstream than normal platelets when injected into normal recipients. A significant correlation between the spleen weight and the decrease of the circulating platelets was observed, although some mice with severe thrombocytopenia had only a moderate spleen enlargement. Thrombocytopenia significantly correlates with the levels of platelet-associated IgG (PAIgG) but not with anti-single-stranded DNA antibodies or circulating immune complexes. Platelets from mice with high levels of PAIgG had a shorter life-span when injected into normal mice than those from mice with low or normal PAIgG. The possibility that PAIgG are partially due to antibodies reacting specifically with platelet membrane components was analyzed. First, F(ab')2 Ig fragments from tolerant mice were shown to bind to normal platelets, in contrast to F(ab')2 Ig fragments from normal mice. Second, some monoclonal antibodies produced by hybridomas derived from tolerant mice reacted in vitro with platelets and induced a transient thrombocytopenia after i.v. injection into normal mice. These data suggest that the thrombocytopenia observed in tolerant mice is the result of a peripheral hyperdestruction of platelets associated with (a) hypersplenism, (b) nonspecific fixation of immunoglobulins, probably as immune complexes and (c) with autoantibodies reacting specifically with platelets. It may represent an interesting model for human chronic idiopathic thrombocytopenia.

Microparticles mediate MRP1 intercellular transfer and the re-templating of intrinsic resistance pathways

Publisher: Elsevier BV

Date: 10-2013

DOI: 10.1016/J.PHRS.2013.07.009

Abstract: Multidrug resistance (MDR) is a major impediment to the overall success of chemotherapy in clinical oncology. MDR has been primarily attributed by the ATP-dependent transmembrane proteins, P-glycoprotein (P-gp, ABCB1) and Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1). These proteins maintain sublethal concentrations of intracellular chemotherapeutics by virtue of their drug efflux capacity. In this study, we report the acquisition and dissemination of functional MRP1 via microparticle (MP) mediated intercellular transfer. After we showed the transfer and functionality of P-gp in drug sensitive recipient cells, we report the transfer and time-dependent functionality of MRP1 in drug sensitive leukaemia cells following exposure to MPs shed by MRP1-overexpressing MDR cells. We also demonstrate a remarkable capacity for MPs shed from cells with a P-gp dominant resistance profile to re-template a pre-existing MRP1 dominant profile in recipient cells. These findings have significance in understanding the molecular basis for tumour dominant phenotypes and introduce potential new strategies and targets for the acquisition of MDR and other deleterious traits.

Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria

Publisher: American Society for Microbiology

Date: 2014

DOI: 10.1128/AAC.02591-12

Abstract: Cerebral malaria (CM) is characterized by a dysregulated immune response that results in endothelial membrane destabilization and increased microparticle (MP) production. Citicoline (CTC) is a membrane stabilizer used for the treatment of neurological disorders. We evaluated the efficacy of CTC as adjunct therapy to aid recovery from experimental CM. We show that CTC reduces MP production in vitro in combination with artesunate in vivo , confers partial protection against CM and prolongs survival.

Requirement for Tumor Necrosis Factor Receptor 2 Expression on Vascular Cells To Induce Experimental Cerebral Malaria

Publisher: American Society for Microbiology

Date: 10-2002

DOI: 10.1128/IAI.70.10.5857-5859.2002

Abstract: Using tumor necrosis factor receptor type 2 (TNFR2)-deficient mice and generating bone marrow chimeras which express TNFR2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for TNFR2 expression on tissue cells to induce lethal cerebral malaria. Thus, TNFR2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria.

Protective Effect of N-Acetylcysteine in Hapten-Induced Irritant and Contact Hypersensitivity Reactions

Publisher: Elsevier BV

Date: 06-1994

DOI: 10.1111/1523-1747.EP12384093

Abstract: The hapten-induced irritant and contact hypersensitivity reactions are experimental models of cutaneous inflammation in which tumor necrosis factor-alpha is an important mediator. N-acetylcysteine is an anti-oxidant that inhibits the action of the nuclear factor-kB, which promotes the transcription of many genes, including the gene for tumor necrosis factor-alpha. We tested the ability of N-acetylcysteine to antagonize the development of the irritant and contact hypersensitivity reactions induced by the epicutaneous application of trinitrochlorobenzene in mice. Systemic and topical treatment with N-acetylcysteine reduced skin swelling in both the irritant and contact hypersensitivity reactions in the latter it also reduced the dermal leukocyte infiltrate. It also reduced the cutaneous expression of the mRNA for tumor necrosis factor-alpha in both conditions. These results show that N-acetylcysteine antagonizes the development of irritant and contact hypersensitivity reactions and that its action includes a reduction in the expression of tumor necrosis factor-alpha mRNA. N-acetylcysteine may be useful in the treatment of cutaneous inflammation mediated by tumor necrosis factor-alpha.

Role of platelet adhesion in homeostasis and immunopathology.

Publisher: BMJ

Date: 08-1997

DOI: 10.1136/MP.50.4.175

Abstract: Various molecules expressed on the surface of platelets have been shown to mediate the protective or deleterious role of these cells in immuno-inflammatory mechanisms. Increasing evidence points to the involvement of the cell adhesion molecules, gpIIb-IIIa, P-selectin, CD31, LFA-1, and CD36 in the interaction between platelets and endothelial cells as well as other cell types. The possible role of these molecules in the ability of platelets to support endothelium and to protect against tumour necrosis factor mediated cytolysis or parasitic invasion are reviewed. The involvement of platelets as effectors of tissue damage in cerebral malaria, lipopolysaccharide induced pathology, and pulmonary fibrosis is also discussed. This has then been extended to include the intercellular mechanisms underpinning their pathogenic role in metastasis, transplant rejection, stroke, brain hypoxia, and related conditions. A better understanding of the complex regulation and hierarchical organisation of these various platelet adhesion molecules may prove useful in the development of new approaches to the treatment of such diseases.

Antiangiogenic Effect of Erythromycin: An In Vitro Model ofBartonella quintanaInfection

Publisher: Oxford University Press (OUP)

Date: 02-2006

DOI: 10.1086/499276

Abstract: Bartonella quintana, the etiological agent of bacillary angiomatosis (BA), causes endothelial cell proliferation. Erythromycin has dramatic effects on BA, and the effects are largely unexplained by the compound's bacteriostatic properties. Our aim here was to evaluate the possibility that erythromycin alters angiogenesis. The effect of erythromycin on B. quintana-induced endothelial cell proliferation was studied using a wild-type strain and an erythromycin-resistant B. quintana mutant. The latter was generated by serial subcultures on blood agar plates. We show that erythromycin significantly inhibits the proliferation of dermal microvascular endothelial cells induced either by wild-type B. quintana or by our erythromycin-resistant mutant. Doxycycline and gentamycin failed to exert such an effect. Finally, we found that the resistant strain harbored a 27-bp insertion in the highly conserved region of the gene encoding the ribosomal protein L4 this insertion may explain the existence of the resistance to erythromycin. The data presented here indicate that erythromycin profoundly down-modulates endothelial cell proliferation irrespective of its bacteriostatic effects and suggest that this may be a key component of the efficacy of the compound in the treatment of patients with BA.

Differentially expressed microRNAs in experimental cerebral malaria and their involvement in endocytosis, adherens junctions, FoxO and TGF-β signalling pathways

Publisher: Springer Science and Business Media LLC

Date: 26-07-2018

DOI: 10.1038/S41598-018-29721-Y

Abstract: Cerebral malaria (CM) is the most severe manifestation of infection with Plasmodium , however its pathogenesis is still not completely understood. microRNA (miRNA) have been an area of focus in infectious disease research, due to their ability to affect normal biological processes, and have been shown to play roles in various viral, bacterial and parasitic infections, including malaria. The expression of miRNA was studied following infection of CBA mice with either Plasmodium berghei ANKA (causing CM), or Plasmodium yoelii (causing severe but non-cerebral malaria (NCM)). Using microarray analysis, miRNA expression was compared in the brains of non-infected (NI), NCM and CM mice. Six miRNA were significantly dysregulated between NCM and CM mice, and four of these, miR-19a-3p, miR-19b-3p, miR-142-3p and miR-223-3p, were further validated by qPCR assays. These miRNA are significantly involved in several pathways relevant to CM, including the TGF-β and endocytosis pathways. Dysregulation of these miRNA during CM specifically compared with NCM suggests that these miRNA, through their regulation of downstream targets, may be vitally involved in the neurological syndrome. Our data implies that, at least in the mouse model, miRNA may play a regulatory role in CM pathogenesis.

Tumor necrosis factor alpha is involved in mouse growth and lymphoid tissue development.

Publisher: Rockefeller University Press

Date: 11-1992

DOI: 10.1084/JEM.176.5.1259

Abstract: Tumor necrosis factor alpha (TNF-alpha), a major mediator of inflammation, also possesses a wide pleiotropism of actions, suggesting its involvement in physiological conditions. TNF-alpha mRNA is present in mouse embryonic tissues and also in fetal thymus and spleen. Repeated injections of a monospecific polyclonal rabbit anti-mouse TNF-alpha antibody in mice, starting either during pregnancy or at birth, led to a severe but transient growth retardation, already present at birth, reaching a 35% decrease in body weight at 3 wk, with complete recovery at 8 wk. The insulin growth factor I (IGF-I) blood levels were decreased to about 50% growth hormone release and other endocrine functions were unaltered. A marked atrophy of the thymus, spleen, and lymph nodes was also observed, with lymphopenia and impaired development of T and B cell peripheral lymphoid structures. The pathways involving TNF-alpha in IGF-I release and early body growth are probably distinct from those by which TNF-alpha participates in early development of lymphoid tissues, where its low physiological release may contribute to enhance lymphoid cell expansion.

The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection

Publisher: Elsevier BV

Date: 03-1989

DOI: 10.1016/0092-8674(89)90676-4

Abstract: Granuloma formation in the liver of mice infected with BCG coincides with local TNF synthesis. Injection of rabbit anti-TNF antibody, after 1 or 2 weeks of infection, dramatically interferes with the development of granulomas (both in number and size, large epithelioid cells failing to appear) and subsequent mycobacterial elimination. Furthermore, fully developed BCG granulomas, after 3 weeks of infection, rapidly regress after anti-TNF treatment. Antibody treatment also prevents or suppresses accumulation of TNF mRNA and protein, which resumes after disappearance of the antibody. Peritoneal macrophages exposed to TNF transiently accumulate TNF mRNA, and show an enhanced increase in TNF mRNA in response to gamma interferon. We propose that TNF released from macrophages in the microenvironment of developing granulomas is involved in a process of auto lification: acting in an autocrine or paracrine way, it enhances its own synthesis and release, thus favoring further macrophage accumulation and differentiation leading to bacterial elimination.

Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-1996

DOI: 10.1097/00003246-199603000-00006

Abstract: The aims of this study were: a) to evaluate plasma concentrations of cytokines and their soluble receptors, as well as antioxidant substances in patients at high risk of developing multiple organ failure b) to investigate early change: and c) to examine the possible prognostic value of these elements. Prospective analysis. Surgical intensive care unit (ICU) of a university hospital. sixteen patients at risk for multiple organ failure. Ten patients developed multiple organ failure and five of them died. Whereas tumor necrosis factor-alpha (TNF-alpha) plasma concentrations were only borderline higher in patients developing multiple organ failure, TNF-soluble receptors 55 and 75 were significantly increased during all ICU days compared with patients not going into organ failure. Interleukin-6 plasma concentrations were higher in patients developing multiple organ failure during the first 2 days after ICU admission. The antioxidant vitamin C was significantly decreased in patients going into multiple organ failure during all ICU days. Other biochemical markers of antioxidant activity, such as vitamin E, copper, and zinc plasma concentrations, did not differ between the two groups. Our data suggest that there is a marked increase in anti-TNF activity and a decrease of antioxidant defense in patients at risk of developing multiple organ failure. The predictive value of plasma concentrations of circulating TNF-soluble receptors and vitamin C in this type of patient needs further evaluation.

Hydrogen peroxide dynamics in subcellular compartments of malaria parasites using genetically encoded redox probes

Publisher: Springer Science and Business Media LLC

Date: 05-09-2017

DOI: 10.1038/S41598-017-10093-8

Abstract: Redox balance is essential for the survival, growth and multiplication of malaria parasites and oxidative stress is involved in the mechanism of action of many antimalarial drugs. Hydrogen peroxide (H 2 O 2 ) plays an important role in redox signalling and pathogen-host cell interactions. For monitoring intra- and subcellular redox events, highly sensitive and specific probes are required. Here, we stably expressed the ratiometric H 2 O 2 redox sensor roGFP2-Orp1 in the cytosol and the mitochondria of Plasmodium falciparum (P. falciparum) NF54- attB blood-stage parasites and evaluated its sensitivity towards oxidative stress, selected antimalarial drugs, and novel lead compounds. In both compartments, the sensor showed reproducible sensitivity towards H 2 O 2 in the low micromolar range and towards antimalarial compounds at pharmacologically relevant concentrations. Upon short-term exposure (4 h), artemisinin derivatives, quinine and mefloquine impacted H 2 O 2 levels in mitochondria, whereas chloroquine and a glucose-6-phosphate dehydrogenase (G6PD) inhibitor affected the cytosol 24 h exposure to arylmethylamino steroids and G6PD inhibitors revealed oxidation of mitochondria and cytosol, respectively. Genomic integration of an H 2 O 2 sensor expressed in subcellular compartments of P. falciparum provides the basis for studying complex parasite-host cell interactions or drug effects with spatio-temporal resolution while preserving cell integrity, and sets the stage for high-throughput approaches to identify antimalarial agents perturbing redox equilibrium.

Regulation of parathyroid hormone-related protein production in a human lung squamous cell carcinoma line

Publisher: Bioscientifica

Date: 11-1994

DOI: 10.1677/JOE.0.1430333

Abstract: The synthesis and release of parathyroid hormone-related protein (PTHrP) could be influenced in a paracrine or autocrine manner by substances present around or inside tumours, such as bone or stromal cell-derived cytokines, factors produced by the tumour itself or by peritumoural inflammatory cells. We investigated the effects of various cytokines known to be synthesized by osteoblasts, stromal cells, leucocytes or cancer cells, on PTHrP production by the human lung squamous cell carcinoma line BEN. The influence of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) was studied, and compared with those of insulin-like growth factors-I and -II (IGF-I, IGF-II), or macrophage- or granulocyte-macrophage colony-stimulating factors (M-CSF, GM-CSF). TNFα caused a 1·9 ±0·1-fold increase in immunoreactive PTHrP production, which was maximal by 24 h of incubation. IL-6 caused a 2·3 ± 0·2-fold increase, which was maximal by 16 h. These effects, which were time- and concentration-dependent, were blocked by monoclonal antibodies raised against the corresponding cytokine. An increase of PTHrP mRNA was found in IL-6-treated cells. IGF-I and IGF-II increased PTHrP production by 2·0± 0·3- and 2·3 ±0·1-fold respectively. Neither M-CSF nor GM-CSF altered PTHrP production up to 64 h of incubation. PTHrP production was not affected by varying extracellular calcium concentrations, but was decreased by incubation with 100 nmol/l dexamethasone. These results indicate that PTHrP production is influenced by various cytokines, suggesting that they may play a role in the onset of hypercalcaemia during the course of malignant disease, and/or the development and extension of bone metastases, through their effect on PTHrP. Journal of Endocrinology (1994) 143 , 333–341

Expression of major histocompatibility complex antigens on mouse brain microvascular endothelial cells in relation to susceptibility to cerebral malaria

Publisher: Wiley

Date: 09-1997

DOI: 10.1046/J.1365-2567.1997.00297.X

Abstract: The physiopathology of experimental cerebral malaria (CM), an acute neurological complication of Plasmodium berghei ANKA (PbA) infection, involves interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), two cytokines that are known to modulate major histocompatibility complex (MHC) molecule expression. The aim of this study was to evaluate whether the genetic susceptibility to CM is related to the constitutive or IFN-gamma-induced expression of MHC molecules on brain microvessels. To this end, brain microvascular endothelial cells (B-MVEC) were isolated from CM-susceptible (CM-S, CBA/J) and resistant (CM-R, BALB/c) mice. By flow cytometry, we found that less than 5% of CM-S B-MVEC constitutively expressed MHC class I molecules, in contrast to up to 90% of CM-R B-MVEC. Upon stimulation with IFN-gamma, the percentage of positive cells for MHC class I molecules in CM-S B-MVEC became comparable to CM-R B-MVEC, but a higher fluorescence intensity existed on CM-S B-MVEC compared with CM-R B-MVEC. MHC class II molecules were not constitutively expressed on B-MVEC from either strain. IFN-gamma-induced expression of MHC class II (I-A, I-E) molecules was significantly higher in CM-S than CM-R B-MVEC both in percentage of positive cells and fluorescence intensity. These data demonstrate that absent or low MHC class I and higher inducibility of MHC class II expression on B-MVEC are associated with the genetic susceptibility to CM.

The Early Innate Immune Response to, and Phagocyte-Dependent Entry of, Cryptococcus neoformans Map to the Perivascular Space of Cortical Post-Capillary Venules in Neurocryptococcosis

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.AJPATH.2018.03.015

Abstract: The innate immune system is the primary defense against cryptococcal infection, but paradoxically it promotes infection of the central nervous system. We performed a detailed longitudinal study of neurocryptococcosis in normal, chimeric, green fluorescent protein phagocyte-positive mice and phagocyte-depleted mice and interrogated the central nervous system innate immune response to Cryptococcus neoformans H99 using confocal microscopy, histology, flow cytometry, and quantification of brain cytokine/chemokines and fungal burdens. C. neoformans was present in the perivascular space (PVS) of post-capillary venules. This was associated with a massive influx of blood-derived monocytes, neutrophils, and T lymphocytes into the PVS and a predominantly proinflammatory cytokine/chemokine response. Phagocytes containing cryptococci were present only in the lumen and corresponding PVS of post-capillary venules. Free cryptococci were observed breaching the glia limitans, the protective barrier between the PVS and the cerebral parenchyma. Parenchymal cryptococcomas were typically in direct contact with post-capillary venules and lacked surrounding immune cell infiltrates. Phagocyte depletion abrogated cryptococcoma formation and PVS infiltrates. Together, these observations suggest that cryptococcomas can originate via phagocyte-dependent transport across post-capillary venular endothelium into the PVS and thence via passage of free cryptococci into the brain. In conclusion, we demonstrate for the first time that the PVS of cortical post-capillary venules is the major site of the early innate immune response to, and phagocyte-dependent entry of, C. neoformans.

Microparticle‐associated nucleic acids mediate trait dominance in cancer

Publisher: Wiley

Date: 30-09-2011

DOI: 10.1096/FJ.11-186817

Abstract: Drug resistance is a major cause of cancer treatment failure, with multidrug resistance (MDR) being the most serious, whereby cancer cells display cross-resistance to structurally and functionally unrelated drugs. MDR is caused by overexpression of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). These transporters act to maintain sublethal intracellular drug concentrations within the cancer cell, making the population treatment unresponsive. Recently, we discovered a novel nongenetic basis to MDR whereby microparticles (MPs) transfer P-gp intercellularly from MDR donor cells to drug-sensitive recipient cells. MPs isolated from MDR leukemia and breast cancer cells were cocultured with their drug-sensitive counterparts. P-gp transfer was assessed by direct immunolabeling, and acquired transcripts and regulatory microRNAs by quantitative real-time PCR. We show that MDR MPs incorporate nucleic acids MPs change recipient cells' transcriptional environment to reflect donor MDR phenotype, and distinct pathways exist among cancers of different origin that may be dependent on donor cells' ABCB1 overexpression. We demonstrate that this pathway exists for both hematological and nonhematological malignancies. By conferring MDR and "retemplating" the transcriptional landscape of recipient cells, MPs provide a novel pathway, having implications in the dissemination and acquisition of deleterious traits in clinical oncology.

Microparticle conferred microRNA profiles - implications in the transfer and dominance of cancer traits

Publisher: Springer Science and Business Media LLC

Date: 08-06-2012

DOI: 10.1186/1476-4598-11-37

Abstract: Microparticles (MPs) are membrane vesicles which are released from normal and malignant cells following a process of budding and detachment from donor cells. MPs contain surface antigens, proteins and genetic material and serve as vectors of intercellular communication. MPs comprise the major source of systemic RNA including microRNA (miRNA), the aberrant expression of which appears to be associated with stage, progression and spread of many cancers. Our previous study showed that MPs carry both transcripts and miRNAs associated with the acquisition of multidrug resistance in cancer. Herein, we expand on our previous finding and demonstrate that MPs carry the transcripts of the membrane vesiculation machinery ( floppase and scramblase ) as well as nucleic acids encoding the enzymes essential for microRNA biogenesis ( Drosha, Dicer and Argonaute ). We also demonstrate using microarray miRNA profiling analysis, the selective packaging of miRNAs ( miR-1228* , miR-1246 , miR-1308 , miR-149* , miR-455-3p , miR-638 and miR-923) within the MP cargo upon release from the donor cells. These miRNAs are present in both haematological and non-haematological cancer cells and are involved in pathways implicated in cancer pathogenesis, membrane vesiculation and cascades regulated by ABC transporters. Our recent findings reinforce our earlier reports that MP transfer ‘re-templates’ recipient cells so as to reflect donor cell traits. We now demonstrate that this process is likely to occur via a process of selective packaging of nucleic acid species, including regulatory nucleic acids upon MP vesiculation. These findings have significant implications in understanding the cellular basis governing the intercellular acquisition and dominance of deleterious traits in cancers.

VEGF111: New insights in tissue invasion

Publisher: Frontiers Media SA

Date: 22-01-2015

DOI: 10.3389/FPHYS.2015.00002

Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor.

Publisher: Proceedings of the National Academy of Sciences

Date: 07-1989

DOI: 10.1073/PNAS.86.14.5572

Abstract: Experimental cerebral malaria (ECM), a lethal hyperacute neurological syndrome associated with high blood levels of tumor necrosis factor, develops in genetically susceptible (CBA/Ca) mice 7 days after infection with Plasmodium berghei ANKA strain. Injections of neutralizing monoclonal antibody against recombinant murine interferon gamma, not later than 4 days after infection, markedly reduced the incidence of ECM and the elevation in serum levels of tumor necrosis factor. This treatment prevented the cerebral lesions (plugging of brain vessels by monocytes, lymphocytes, and parasitized erythrocytes). In contrast, the extent of macrophage infiltration in lymphoid organs (which is a characteristic feature of mice developing ECM), as well as the course of infection, remained unaffected by the antibody treatment. Protected mice died at a later time of severe anemia and overwhelming parasitemia, the usual outcome of P. berghei infection in mice that are not susceptible to ECM. The present data indicate that interferon gamma constitutes an important link in the cytokine network that leads to brain vessel inflammation in experimental malaria. It is proposed that interferon gamma released by activated CD4+ T cells acts by augmenting both production and action of tumor necrosis factor.

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

Publisher: American Society for Microbiology

Date: 06-2017

DOI: 10.1128/IAI.00941-16

Abstract: The resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. While early effector T cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acute malaria infections is not fully understood. In this study, we have determined the contribution of IL-10R signaling to the regulation of immune responses during Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM). We show that antibody-mediated blockade of the IL-10R during P. berghei ANKA infection in ECM-resistant BALB/c mice leads to lified T cell activation, higher serum gamma interferon (IFN-γ) concentrations, enhanced intravascular accumulation of both parasitized red blood cells and CD8 + T cells to the brain, and an increased incidence of ECM. Importantly, the pathogenic effects of IL-10R blockade during P. berghei ANKA infection were reversible by depletion of T cells and neutralization of IFN-γ. Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-mediated pathology during potentially lethal malaria infections.

Is TNF beneficial or deleterious in toxoplasmic encephalitis?

Publisher: Elsevier BV

Date: 10-1992

DOI: 10.1016/0169-4758(92)90062-7

Brain microvascular endothelial cells and leukocytes derived from patients with multiple sclerosis exhibit increased adhesion capacity

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-1997

DOI: 10.1097/00001756-199702100-00010

Abstract: The adhesion properties of brain microvascular endothelial cells (MVEC) and leukocytes derived from patients with multiple sclerosis (MS) were investigated. Leukocytes and brain MVEC from MS patients exhibited significantly higher adhesion capacity than the same cells isolated from normal donors. Flow cytometry showed that MS-derived brain MVEC constitutively expressed higher levels of ICAM-1 and contained an increased proportion of MHC class II positive cells than normal brain MVEC. In contrast, no difference was seen for vascular cell adhesion molecule-1 and endothelial cell leukocyte adhesion molecule-1. Circulating leukocytes from MS patients expressed higher levels of LFA-1, a ligand of intercellular adhesion molecule-1 (ICAM-1), than did normal leukocytes. The data presented here suggest that the ICAM-1/LFA-1 interaction may determine cytoadherence of leukocytes to brain MVEC in MS.

Endothelial Microparticles Interact with and Support the Proliferation of T Cells

Publisher: The American Association of Immunologists

Date: 10-2014

DOI: 10.4049/JIMMUNOL.1303431

Abstract: Endothelial cells closely interact with circulating lymphocytes. Aggression or activation of the endothelium leads to an increased shedding of endothelial cell microparticles (MP). Endothelial MP (EMP) are found in high plasma levels in numerous immunoinflammatory diseases, such as atherosclerosis, sepsis, multiple sclerosis, and cerebral malaria, supporting their role as effectors and markers of vascular dysfunction. Given our recently described role for human brain microvascular endothelial cells (HBEC) in modulating immune responses, we investigated how HBEC-derived MP could interact with and support the proliferation of T cells. Like their mother cells, EMP expressed molecules important for Ag presentation and T cell costimulation, that is, β2-microglobulin, MHC II, CD40, and ICOSL. HBEC were able to take up fluorescently labeled Ags with EMP also containing fluorescent Ags, suggestive of Ag carryover from HBEC to EMP. In cocultures, fluorescently labeled EMP from resting or cytokine-stimulated HBEC formed conjugates with both CD4+ and CD8+ subsets, with higher proportions of T cells binding EMP from cytokine-stimulated cells. The increased binding of EMP from cytokinestimulated HBEC to T cells was VCAM-1 and ICAM-1 dependent. Finally, in CFSE T cell proliferation assays using anti-CD3 mAb or T cell mitogens, EMP promoted the proliferation of CD4+ T cells and that of CD8+ T cells in the absence of exogenous stimuli and in the T cell mitogenic stimulation. Our findings provide novel evidence that EMP can enhance T cell activation and potentially ensuing Ag presentation, thereby pointing toward a novel role for MP in neuroimmunological complications of infectious diseases.

Biochemical markers of nutritional status and childhood malaria severity in Cameroon

Publisher: Cambridge University Press (CUP)

Date: 09-07-2010

DOI: 10.1017/S0007114510001510

Abstract: To investigate the part played by undernutrition in malaria severity, some biomarkers of nutritional status were assessed in children with severe malarial anaemia (MA) and cerebral malaria (CM) in comparison with healthy children or those with uncomplicated malaria. Undernutrition was assessed using the weight-for-age Z score (WAZ). Retinol was determined by HPLC lipid profile, Ca, Mg and albumin were determined by spectrophotometry. Severe and moderate undernutritions were more prevalent in children with MA and those with the combined symptoms of CM and MA, but not in those with CM alone. Some perturbations were noticed in the lipid profile, but most of the values remained within the normal ranges. The risk of vitamin A deficiency, as assessed by plasma retinol concentration, was noteworthy in children with severe malaria: 0·48 × 10 − 6 and 0·50 × 10 − 6 mol/l, respectively, in children with MA and CM (reference value: ·7 × 10 − 6 mol/l). A significant difference was obtained for retinol values after an ANOVA of all the groups ( P = 0·0029), with the value in the MA group being significantly low than that in the control group ( P 0·05) likewise, a significant difference was obtained after comparison of all the groups for Mg and albumin ( P = 0·0064 and 0·0082, respectively). Despite their low number ( n 6), fatal cases of CM had a normal mean WAZ on admission, but low values of retinol, albumin and HDL:LDL ratio. Despite these associations, undernutrition itself did not appear to be a primary factor associated with fatal outcome.

Platelets Alter Gene Expression Profile in Human Brain Endothelial Cells in an In Vitro Model of Cerebral Malaria

Publisher: Public Library of Science (PLoS)

Date: 16-05-2011

DOI: 10.1371/JOURNAL.PONE.0019651

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

Publisher: Proceedings of the National Academy of Sciences

Date: 29-01-2008

DOI: 10.1073/PNAS.0706867105

Abstract: We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood–brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation–coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.

Serum Profiles of Interleukin-6, Interleukin-8, and Interleukin-10 in Patients with Severe and Mild Acute Pancreatitis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-1999

DOI: 10.1097/00006676-199905000-00007

Abstract: Excessive leukocyte activation has been proposed as a key mechanism in the onset of acute pancreatitis. In this study, we assessed the systemic release of various inflammatory mediators and tried to identify differences between patients with mild and severe disease. In a prospective study, 19 patients admitted for severe acute pancreatitis were compared with 24 patients with mild pancreatitis. Serum levels of interleukin-6 (IL-6), IL-8, and IL-10 were determined at the time of admission, and on days 1, 2, and 5 after hospitalization. Severity of pancreatitis was determined according to the Atlanta criteria. IL-6 levels peaked on admission in both groups with significant differences (p < 0.05) from days 0-2. IL-8 levels increased from day 0 in severe cases, and from day 1 in mild cases, to reach a plateau between days 2 and 5 significant differences were observed on days 0 and 1. IL-10 was highest on day 0 it decreased rapidly in mild cases but stayed significantly higher from days 1 to 5 in severe cases. These findings provide new evidence on the role of mediators of the inflammatory/antiinflammatory balance in acute pancreatitis. These molecules appear to be valuable early markers of severity.

An improved method for isolation of microvascular endothelial cells from normal and inflamed human lung

Publisher: Springer Science and Business Media LLC

Date: 08-1998

DOI: 10.1007/S11626-998-0112-Z

Abstract: Microvascular endothelial cells (MVEC), which differ from large vessel endothelial cells, have been isolated successfully from lungs of various species, including man. However, contamination by nonendothelial cells remains a major problem in spite of several technical improvements. In view of the organ specificity of MVEC, endothelial cells should be derived from the tissue involved in the diseases one wishes to study. Therefore, to investigate some of the immunopathological mechanisms leading to acute respiratory distress syndrome (ARDS), we have attempted to isolate lung MVEC from patients undergoing thoracic surgery for lung carcinoma and patients dying of ARDS. The method described here includes four main steps: (1) full digestion of pulmonary tissue with trypsin and collagenase, (2) aggregation of MVEC induced by human plasma, (3) Percoll density centrifugation, and (4) selection and transfer of MVEC after local digestion with trypsin/EDTA under light microscopy. Normal and ARDS-derived lung MVEC purified by this technique presented contact inhibition (i.e., grew in monolayer), and expressed classical endothelial markers, including von Willebrand factor (vWF), platelet endothelial cell adhesion molecule 1(PECAM-1, CD31), and transcripts for the angiotensin converting enzyme (ACE). The cells also formed capillarylike structures, took up high levels of acetylated low-density lipoprotein (Ac-LDL), and exhibited ELAM-1 inducibility in response to TNF. Contaminant cells, such as fibroblasts, smooth muscle cells, or pericytes, were easily recognized on the basis of morphology and were eliminated by selection of plasma-aggregated cells under light microscopy. The technique presented here allows one to study the specific involvement and contribution of pulmonary endothelium in various lung diseases.

Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease.

Publisher: Rockefeller University Press

Date: 11-1987

DOI: 10.1084/JEM.166.5.1280

Abstract: Lethally irradiated mice were injected with semiallogeneic, T-depleted bone marrow cells and an amount of peripheral T lymphocytes sufficient to induce graft-vs.-host disease (GVHD) becoming apparent on the second week after the graft and leading to an increasing mortality rate within the following weeks (greater than 90% mortality within 80 d). Mice receiving bone marrow cells alone had no GVHD and were used as controls. Beginning on day 8, mice with GVHD were injected weekly with 2 mg of either rabbit anti-mouse recombinant tumor necrosis factor/cachectin (TNF-alpha) IgG, or normal rabbit IgG. On the 16-18th d, mice were killed to examine the skin and intestinal lesions of the acute phase of GVHD. The anti-TNF treatment resulted in an almost complete prevention of the severe lesions seen in the mice treated with normal rabbit IgG, i.e., the skin epidermal cell necrosis, foci of lichenoid hyperplastic reactions, and loss of the hypodermic fat in the gut dilatation with marked flattening of the villi and elevation of the crypts, with increased numbers of mitoses and isolated crypt cell necrosis. In addition to preventing these acute lesions, anti-TNF treatment resulted in a significantly decreased mortality (approximately 70% survival at 80 d). These results suggest that during acute GVHD, the activation of grafted lymphocytes leads to a local release of TNF in the cutaneous and intestinal mucosae, which induces epithelial cell alterations and increases the inflammatory reaction.

Production, Fate and Pathogenicity of Plasma Microparticles in Murine Cerebral Malaria

Publisher: Public Library of Science (PLoS)

Date: 20-03-2014

DOI: 10.1371/JOURNAL.PPAT.1003839

Nitric oxide and cerebral malaria

Publisher: Elsevier BV

Date: 12-1992

DOI: 10.1016/0140-6736(92)92812-T

Current perspectives on the mechanism of action of artemisinins

Publisher: Elsevier BV

Date: 12-2006

DOI: 10.1016/J.IJPARA.2006.07.011

Abstract: Artemisinin derivatives are the most recent single drugs approved and introduced for public antimalarial treatment. Although their recommended use is for treatment of Plasmodium falciparum infection, these drugs also act against other parasites, as well as against tumor cells. The mechanisms of action attributed to artemisinin include interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis. Artemisinin combination therapies are currently the preferred treatment for malaria. These combinations may prevent the induction of parasite drug resistance. However, in view of the multiple mechanisms involved, especially when additional drugs are used, the combined therapy should be carefully examined for antagonistic effects. It is now a general theory that the crucial mechanism is interference with plasmodial SERCA. Therefore, future development of resistance may be associated with overproduction or mutations of this transporter. However, a general mechanism, such as alterations in general drug transport pathways, is feasible. In this article, we review the evidence for each mechanism of action suggested.

TNF in pathology: old facts and new questions

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/S0923-2494(93)80073-8

A potential role for interleukin-33 and γ-epithelium sodium channel in the pathogenesis of human malaria associated lung injury

Publisher: Springer Science and Business Media LLC

Date: 05-10-2015

DOI: 10.1186/S12936-015-0922-X

Diagnostic Value of Procalcitonin, Interleukin-6, and Interleukin-8 in Critically Ill Patients Admitted with Suspected Sepsis

Publisher: American Thoracic Society

Date: 08-2001

DOI: 10.1164/AJRCCM.164.3.2009052

Abstract: To assess the diagnostic value of procalcitonin (PCT), interleukin (IL)-6, IL-8, and standard measurements in identifying critically ill patients with sepsis, we performed prospective measurements in 78 consecutive patients admitted with acute systemic inflammatory response syndrome (SIRS) and suspected infection. We estimated the relevance of the different parameters by using multivariable regression modeling, likelihood-ratio tests, and area under the receiver operating characteristic curves (AUC). The final diagnosis was SIRS in 18 patients, sepsis in 14, severe sepsis in 21, and septic shock in 25. PCT yielded the highest discriminative value, with an AUC of 0.92 (CI, 0.85 to 1.0), followed by IL-6 (0.75 CI, 0.63 to 0.87), and IL-8 (0.71 CI, 0.59 to 0.83 p < 0.001). At a cutoff of 1.1 ng/ml, PCT yielded a sensitivity of 97% and a specificity of 78% to differentiate patients with SIRS from those with sepsis-related conditions. Median PCT concentrations on admission (ng/ ml, range) were 0.6 (0 to 5.3) for SIRS 3.5 (0.4 to 6.7) for sepsis 6.2 (2.2 to 85) for severe sepsis and 21.3 (1.2 to 654) for septic shock (p < 0.001). The addition of PCT to a model based solely on standard indicators improved the predictive power of detecting sepsis (likelihood ratio test p = 0.001) and increased the AUC value for the routine value-based model from 0.77 (CI, 0.64 to 0.89) to 0.94 (CI, 0.89 to 0.99 p = 0.002). In contrast, no additive effect was seen for IL-6 (p = 0.56) or IL-8 (p = 0.14). Elevated PCT concentrations appear to be a promising indicator of sepsis in newly admitted, critically ill patients capable of complementing clinical signs and routine laboratory parameters suggestive of severe infection.

The CTLA-4 and PD-1/PD-L1 Inhibitory Pathways Independently Regulate Host Resistance to Plasmodium-induced Acute Immune Pathology

Publisher: Public Library of Science (PLoS)

Date: 02-02-2012

DOI: 10.1371/JOURNAL.PPAT.1002504

The role of reactive nitrogen intermediates in modulation of gametocyte infectivity of rodent malaria parasites

Publisher: Wiley

Date: 1993

DOI: 10.1111/J.1365-3024.1993.TB00568.X

Abstract: Direct feeding of Anopheles stephensi mosquitoes on mice infected with Plasmodium vinckei petteri showed that, during the periods of schizogony in the blood, the infectivity of gametocytes was markedly reduced. This could be prevented by prior injection of the L-arginine analogue, Nw-nitro-L-arginine (NwNLA) showing that the altered infectivity was due to reactive nitrogen intermediates (RNI). Similar effects on transmission of P. yoelii nigeriensis were demonstrated in vitro by membrane feeding of the mosquitoes. The in vitro reduction in infectivity could be reversed by injecting the L-arginine analogue either into the infected mouse donor of serum, or into the membrane feeding chamber. Elevated levels of TNF and IL-6 were demonstrated during the course of infection but did not correlate well with nitrogen radical activity. Similarly, direct measurements of NO2- and NO3- did not reflect the nitrogen radical activity revealed by addition of the specific L-arginine analogue.

Infrared spectroscopic characterization of monocytic microvesicles (microparticles) released upon lipopolysaccharide stimulation

Publisher: Wiley

Date: 17-03-2017

DOI: 10.1096/FJ.201601272R

Dysregulation of pulmonary endothelial protein C receptor and thrombomodulin in severe falciparum malaria-associated ARDS relevant to hemozoin

Publisher: Public Library of Science (PLoS)

Date: 21-07-2017

DOI: 10.1371/JOURNAL.PONE.0181674

Targeting Vascular Endothelial-Cadherin in Tumor-Associated Blood Vessels Promotes T-cell–Mediated Immunotherapy

Publisher: American Association for Cancer Research (AACR)

Date: 14-08-2017

DOI: 10.1158/0008-5472.CAN-16-3129

Abstract: T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell–specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8+ T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature. Cancer Res 77(16) 4434–47. ©2017 AACR.

Tumor Necrosis Factor (Cachectin) as an Essential Mediator in Murine Cerebral Malaria

Publisher: American Association for the Advancement of Science (AAAS)

Date: 04-09-1987

DOI: 10.1126/SCIENCE.3306918

Abstract: Tumor necrosis factor, or cachectin (TNF-alpha), a protein with a wide range of biological activities, is produced mainly by macrophages and may be important in inflammatory processes. The role of TNF-alpha in the pathogenesis of cerebral malaria was investigated in a murine model. Most CBA mice infected with Plasmodium berghei anka die between days 6 and 14 with acute neurological manifestations unrelated to the level of parasitemia, whereas mice of some other strains have malaria of the same severity that ends in death after 3 to 4 weeks without neurological manifestations. The activity of serum TNF-alpha was considerably increased in CBA/Ca mice with cerebral malaria but not in Plasmodium berghei-infected mice that did not develop this complication. One injection of rabbit antibody to TNF-alpha on day 4 or 7 fully protected infected mice from cerebral malaria without modifying the parasitemia, whereas immunoglobulins from normal rabbit had no effect. In mice with cerebral malaria, the cerebral vessels showed focal accumulations of packed macrophages often containing infected erythrocytes this lesion was not seen in mice treated with antibody to TNF-alpha or in untreated mice without cerebral malaria. These findings indicate that TNF-alpha has an important role in the pathogenesis of cerebral malaria in this murine model and suggest that local accumulation and activation of macrophages may lead to the predominance of lesions in the central nervous system.

Correction: The Brain Microvascular Endothelium Supports T Cell Proliferation and Has Potential for Alloantigen Presentation

Publisher: Public Library of Science (PLoS)

Date: 22-04-2013

DOI: 10.1371/ANNOTATION/971919C7-D831-4C8C-9DBF-3AD7B2C1F667

Endotoxin-Induced Monocytic Microparticles Have Contrasting Effects on Endothelial Inflammatory Responses

Publisher: Public Library of Science (PLoS)

Date: 19-03-2014

DOI: 10.1371/JOURNAL.PONE.0091597

Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide‐induced lethality

Publisher: Wiley

Date: 11-1991

DOI: 10.1002/EJI.1830211134

Abstract: The in vivo efficacy of human recombinant soluble tumor necrosis factor (TNF) receptor protein to prevent and to treat lipopolysaccharide (LPS)-induced lethal toxicity in D-galactosamine-treated mice was investigated. Chimeric proteins of the receptor extracellular domains fused to the hinge region of human IgG3 were expressed in myeloma cells (rsTNFR-h gamma 3). The fusion proteins had a disulfide-bonded dimeric structure. Upon intravenous injection, their serum concentration decreased relatively slowly after an initial phase of rapid elimination. D-galactosamine-sensitized mice were fully protected from the toxic effects of LPS, if the animal were pretreated with rsTNFR-h gamma 3 at 20 micrograms/animal. Partial protection was seen at significantly lower doses and when rsTNFR-h gamma 3 was given up to 3 h after LPS.

Cerebral malaria: role of microparticles and platelets in alterations of the blood–brain barrier

Publisher: Elsevier BV

Date: 05-2006

DOI: 10.1016/J.IJPARA.2006.02.005

Abstract: Brain lesions of cerebral malaria (CM) are characterised by a sequestration of Plasmodium falciparum-parasitised red blood cells (PRBC), leucocytes and platelets within brain microvessels, by an excessive release of pro-inflammatory cytokines as well as by disruption of the blood-brain barrier (BBB). We evaluated the possibility that PRBC and platelets interact and induce functional alterations in brain endothelium. Using an in vitro model of endothelial lesion, we showed that platelets can act as bridges between PRBC and endothelial cells (EC) allowing the binding of PRBC to endothelium devoid of cytoadherence receptors. Furthermore, platelets potentiated the cytotoxicity of PRBC for brain EC by inducing an alteration of the integrity of their monolayer and increasing their apoptosis. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM. Another aspect of inflammatory and infectious diseases is that they often lead to activation of vascular and blood cells. Such activation results in an enhanced vesiculation, i.e. the release of circulating microparticles (MP). We thus explored plasma levels of endothelial MP in Malawian children with malaria. Plasma MP numbers were markedly increased on admission only in patients with severe malaria complicated with coma. Using the experimental mouse model of CM, we evaluated the pathogenic implications of MP using genetically deficient mice in which the capacity to vesiculate is impaired. Such mice, lacking the ABCA-1 gene, upon infection by Plasmodium berghei ANKA, showed complete resistance to CM. When purified from infected susceptible animals, MP were able to reduce normal plasma clotting time and to significantly enhance tumour necrosis factor release from naïve macrophages. Altogether these data provide a novel insight into the pathogenic mechanisms leading to the neurological syndrome. The finding that ABCA-1 gene deletion confers complete protection against cerebral pathology, linked to an impaired MP production, provides new potential targets for therapeutic amelioration of severe malaria.

Malaria: modification of the red blood cell and consequences in the human host

Publisher: Wiley

Date: 28-05-2011

DOI: 10.1111/J.1365-2141.2011.08755.X

Effects of Aggregatibacter actinomycetemcomitans leukotoxin on endothelial cells

Publisher: Elsevier BV

Date: 08-2013

DOI: 10.1016/J.MICPATH.2013.05.001

The ins and outs of phosphosignalling in Plasmodium: Parasite regulation and host cell manipulation

Publisher: Elsevier BV

Date: 07-2016

DOI: 10.1016/J.MOLBIOPARA.2016.05.006

Abstract: Signal transduction and kinomics have been rapidly expanding areas of investigation within the malaria research field. Here, we provide an overview of phosphosignalling pathways that operate in all stages of the Plasmodium life cycle. We review signalling pathways in the parasite itself, in the cells it invades, and in other cells of the vertebrate host with which it interacts. We also discuss the potential of these pathways as novel targets for antimalarial intervention.

Cell vesiculation and immunopathology: implications in cerebral malaria

Publisher: Elsevier BV

Date: 07-2006

DOI: 10.1016/J.MICINF.2006.04.006

Abstract: Microparticles are plasma membrane fragments that are generated and released under physiological conditions. They are also released when tissue and/or systemic homeostasis is disrupted. These microparticles display different physiological features of the cells from which they originate. They are detected in some pathological conditions, but rarely suspected of participating in the disease's pathogenesis. In the present review, we summarise data about the production of the microparticles, their biological significance and potential role during microorganism-driven processes, especially in cerebral malaria.

Cytoadherence of Plasmodium berghei-Infected Red Blood Cells to Murine Brain and Lung Microvascular Endothelial Cells In Vitro

Publisher: American Society for Microbiology

Date: 11-2013

DOI: 10.1128/IAI.00428-13

Abstract: Sequestration of infected red blood cells (iRBC) within the cerebral and pulmonary microvasculature is a hallmark of human cerebral malaria (hCM). The interaction between iRBC and the endothelium in hCM has been studied extensively and is linked to the severity of malaria. Experimental CM (eCM) caused by Plasmodium berghei ANKA reproduces most features of hCM, although the sequestration of RBC infected by P. berghei ANKA (PbA-iRBC) has not been completely delineated. The role of PbA-iRBC sequestration in the severity of eCM is not well characterized. Using static and flow cytoadherence assays, we provide the first direct in vitro evidence for the binding of PbA-iRBC to murine brain and lung microvascular endothelial cells (MVEC). We found that basal PbA-iRBC cytoadherence to MVECs was significantly higher than that of normal red blood cells (NRBC) and of RBC infected with P. berghei K173 (PbK173-iRBC), a strain that causes noncerebral malaria (NCM). MVEC prestimulation with tumor necrosis factor (TNF) failed to promote any further significant increase in mixed-stage iRBC adherence. Interestingly, enrichment of the blood for mature parasites significantly increased PbA-iRBC binding to the MVECs prestimulated with TNF, while blockade of VCAM-1 reduced this adhesion. Our study provides evidence for the firm, flow-resistant binding to endothelial cells of iRBC from strain ANKA-infected mice, which develop CM, and for less binding of iRBC from strain K173-infected mice, which develop NCM. An understanding of P. berghei cytoadherence may help elucidate the importance of sequestration in the development of CM and aid the development of antibinding therapies to help reduce the burden of this syndrome.

Imaging Experimental Cerebral MalariaIn Vivo: Significant Role of Ischemic Brain Edema

Publisher: Society for Neuroscience

Date: 10-08-2005

DOI: 10.1523/JNEUROSCI.1002-05.2005

Abstract: The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.

Bronchial epithelial cell extracellular vesicles ameliorate epithelial–mesenchymal transition in COPD pathogenesis by alleviating M2 macrophage polarization

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.NANO.2019.03.010

Abstract: Chronic obstructive pulmonary disease (COPD) is partly characterized as epithelial-mesenchymal transition (EMT)-related airflow limitation. Extracellular vesicles (EVs) play crucial roles in the crosstalk between cells, affecting many diseases including COPD. Up to now, the roles of EVs in COPD are still debated. As we found in this investigation, COPD patients have higher miR-21 level in total serum EVs. EMT occurs in lungs of COPD mice. Furthermore, bronchial epithelial cells (BEAS-2B) could generate EVs with less miR-21 when treated with cigarette smoke extract (CSE), impacting less on the M2-directed macrophage polarization than the control-EVs (PBS-treated) according to EVs miR-21 level. Furthermore, the EMT processes in BEAS-2B cells were enhanced with the M2 macrophages proportion when co-cultured. Collectively, these results demonstrate that CSE-treated BEAS-2B cells could alleviate M2 macrophages polarization by modulated EVs, and eventually relieve the EMT process of BEAS-2B cells themselves under COPD pathogenesis, revealing a novel compensatory role of them in COPD.

Reduced Transendothelial Migration of Monocytes Infected byCoxiella burnetii

Publisher: American Society for Microbiology

Date: 06-2000

DOI: 10.1128/IAI.68.6.3784-3786.2000

Abstract: The migratory properties of THP1 monocytes infected by Coxiella burnetii were determined in a transmigration assay across a human microvascular endothelial cell monolayer. Transendothelial migration of monocytes infected by virulent, but not avirulent, C. burnetii was inhibited. This inhibition was observed in spite of conserved adherence properties of infected monocytes.

TNF inhibits malaria hepatic stages in vitro via synthesis of IL-6

Publisher: Oxford University Press (OUP)

Date: 1991

DOI: 10.1093/INTIMM/3.4.317

Abstract: We examined the capacity of murine recombinant tumor necrosis factor (rmTNF) to induce an inhibitory effect at the hepatic stage on malaria induced by Plasmodium yoelii sporozoites. When injected three times, 1.0 micrograms of rmTNF was found to protect 78% of mice against a sporozoite challenge. In contrast, whatever the dose and the schedule of administration, no inhibition was observed when purified hepatocyte cultures were infected with P. yoelii. The addition of non-parenchymal hepatic cells to hepatocyte cultures restored the capacity of TNF to modulate hepatic stage development, leading to up to 44% inhibition. Antibodies to interleukin 6 reversed the anti-parasite activity in the co-culture system.

Transgenic mice expressing high levels of soluble TNF‐R1 fusion protein are protected from lethal septic shock and cerebral malaria, and are highly sensitive to Listeria monocytogenes and Le