ORCID Profile
0000-0002-3044-9488
Current Organisation
James Cook University
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Publisher: American Society for Microbiology
Date: 06-2012
DOI: 10.1128/IAI.00149-12
Abstract: Staphylococcus aureus is a leading cause of severe endophthalmitis, which often results in vision loss in some patients. Previously, we showed that Toll-like receptor 2 (TLR2) ligand pretreatment prevented the development of staphylococcal endophthalmitis in mice and suggested that microglia might be involved in this protective effect (Kumar A, Singh CN, Glybina IV, Mahmoud TH, Yu FS. J. Infect. Dis. 201:255–263, 2010). The aim of the present study was to understand how microglial innate response is modulated by TLR2 ligand pretreatment. Here, we demonstrate that S. aureus infection increased the CD11b + CD45 + microglial/macrophage population in the C57BL/6 mouse retina. Using cultured primary retinal microglia and a murine microglial cell line (BV-2), we found that these cells express TLR2 and that its expression is increased upon stimulation with bacteria or an exclusive TLR2 ligand, Pam3Cys. Furthermore, challenge of primary retinal microglia with S. aureus and its cell wall components peptidoglycan (PGN) and lipoteichoic acid (LTA) induced the secretion of proinflammatory mediators (tumor necrosis factor alpha [TNF-α] and MIP-2). This innate response was attenuated by a function-blocking anti-TLR2 antibody or by small interfering RNA (siRNA) knockdown of TLR2. In order to assess the modulation of the innate response, microglia were pretreated with a low dose (0.1 or 1 μg/ml) of Pam3Cys and then challenged with live S. aureus . Our data showed that S. aureus -induced production of proinflammatory mediators is dramatically reduced in pretreated microglia. Importantly, microglia pretreated with the TLR2 agonist phagocytosed significantly more bacteria than unstimulated cells. Together, our data suggest that TLR2 plays an important role in retinal microglial innate response to S. aureus , and its sensitization inhibits inflammatory response while enhancing phagocytic activity.
Publisher: MDPI AG
Date: 10-02-2019
DOI: 10.3390/TROPICALMED4010033
Abstract: Papua New Guinea (PNG) has a high burden of tuberculosis (TB), including drug-resistant TB (DR-TB). DR-TB has been identified in patients in Western Province, although there has been limited study outside the provincial capital of Daru. This study focuses on the Balimo region of Western Province, aiming to identify the proportion of DR-TB, and characterise Mycobacterium tuberculosis (MTB) drug resistance-associated gene mutations. Sputum s les were investigated for MTB infection using published molecular methods. DNA from MTB-positive s les was lified and sequenced, targeting the rpoB and katG genes to identify mutations associated with rif icin and isoniazid resistance respectively. A total of 240 sputum s les were collected at Balimo District Hospital (BDH). Of these, 86 were classified as positive based on the results of the molecular assays. For s les where rpoB sequencing was successful, 10.0% (5/50, 95% CI 4.4–21.4%) were considered rif icin-resistant through detection of drug resistance-associated mutations. We have identified high rates of presumptive DR-TB in the Balimo region of Western Province, PNG. These results emphasise the importance of further surveillance, and strengthening of diagnostic and treatment services at BDH and throughout Western Province, to facilitate detection and treatment of DR-TB, and limit transmission in this setting.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2014
Abstract: Stromal cell-derived factor-1 (SDF-1) is expressed in pre-adipocytes but its role is unknown. We investigated butyrate (a histone deacetylase inhibitor--HDACi) and other short-chain fatty acids (SCFA) in the regulation of SDF-1. We further investigated whether effects of SCFA were signalled through G protein-coupled receptors FFA2 and FFA3. SDF-1 mRNA expression and protein secretion were studied in 3T3-L1 cells and human pre-adipocytes. SDF-1 was abundant, with mRNA and protein levels increased by butyrate. This was replicated with acetate and propionate, but not with trichostatin or valproate. Trichostatin inhibited SDF-1 secretion. Pertussis toxin blocked stimulation by butyrate. The order of potency of SCFA in stimulating SDF-1 (C3 > C4 > C2) is consistent with action through FFA3. Silencing the FFA3 gene abolished butyrate-stimulated SDF-1 expression and secretion. FFA3 was expressed in both pre-adipocytes and adipocytes, while FFA2 was expressed in adipocytes only. SDF-1 expression was low in murine macrophage J774.2 cells, while the SDF-1 receptor CXCR4 was absent from 3T3-L1 cells but abundant in J774.2 macrophages. In human pre-adipocytes, FFA3 was also expressed and SCFA increased SDF-1 secretion. SDF-1 and CXCR4 may mediate the interaction between adipose stromal cells and macrophages. Effects of SCFA are mediated through FFA3, but not histone deacetylase inhibition.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-03-2020
Abstract: We provide an empirical model to evaluate and rank data obtained from preclinical tuberculosis vaccine studies.
Publisher: American Society for Microbiology
Date: 06-2012
DOI: 10.1128/IAI.00212-12
Abstract: Melioidosis is a potentially fatal disease caused by the bacterium Burkholderia pseudomallei . Type 2 diabetes (T2D) is the most common comorbidity associated with melioidosis. B. pseudomallei isolates from melioidosis patients with T2D are less virulent in animal models than those from patients with melioidosis and no identifiable risk factors. We developed an ex vivo whole-blood assay as a tool for comparison of early inflammatory profiles generated by T2D and nondiabetic (ND) in iduals in response to a B. pseudomallei strain of low virulence. Peripheral blood from in iduals with T2D, with either poorly controlled glycemia (PC-T2D [ n = 6]) or well-controlled glycemia (WC-T2D [ n = 8]), and healthy ND ( n = 13) in iduals was stimulated with B. pseudomallei . Oxidative burst, myeloperoxidase (MPO) release, expression of pathogen recognition receptors (TLR2, TLR4, and CD14), and activation markers (CD11b and HLA-DR) were measured on polymorphonuclear (PMN) leukocytes and monocytes. Concentrations of plasma inflammatory cytokine (interleukin-6 [IL-6], IL-12p70, tumor necrosis factor alpha [TNF-α], monocyte chemoattractant protein 1 [MCP-1], IL-8, IL-1β, and IL-10) were also determined. Following stimulation, oxidative burst and MPO levels were significantly elevated in blood from PC-T2D subjects compared to controls. Differences were also observed in expression of Toll-like receptor 2 (TLR2), CD14, and CD11b on phagocytes from T2D and ND in iduals. Levels of IL-12p70, MCP-1, and IL-8 were significantly elevated in blood from PC-T2D subjects compared to ND in iduals. Notably, differential inflammatory responses of PC-T2D, WC-T2D, and ND in iduals to B. pseudomallei occur independently of bacterial load and confirm the efficacy of this model of T2D-melioidosis comorbidity as a tool for investigation of dysregulated PMN and monocyte responses to B. pseudomallei underlying susceptibility of T2D in iduals to melioidosis.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Oxford University Press (OUP)
Date: 03-2011
Publisher: Wiley
Date: 06-11-2009
Publisher: Proceedings of the National Academy of Sciences
Date: 10-08-2020
Abstract: Tuberculosis (TB) susceptibility and disease are significantly exacerbated in people with type 2 diabetes. The underlying mechanisms are incompletely understood, and it is not known if new TB vaccine candidates will be safe and provide protection in the context of diabetes. Using a long-term diet-induced murine model of type 2 diabetes, we demonstrate that increased susceptibility to TB is caused by impaired mycobacterial recognition and killing in the diabetic lung. Importantly, we show that mucosal vaccination of diabetic mice with Bacillus Calmette–Guérin (BCG) strains expressing the ESX-1 secretion system from Mycobacterium tuberculosis can overcome this defect and provide superior immunity against TB. Our data warrant a consideration of ESX-1–containing BCG strains as effective TB vaccines in older in iduals and diabetics.
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 2015
Publisher: Elsevier BV
Date: 1995
Publisher: Centers for Disease Control and Prevention (CDC)
Date: 05-2017
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.EJVS.2013.12.020
Abstract: Peripheral arterial disease (PAD) is principally caused by atherosclerosis, an established inflammatory disease. Total white cell count (TWCC) is a marker of inflammation and has been associated with outcomes for patients with inflammatory diseases. The aim of this systematic review was to assess the association of TWCC with mortality and major adverse events (MAEs) in PAD patients. Studies investigating the association of TWCC with outcome in patients with PAD were identified by a literature search using the Medline and Cochrane databases. To be eligible for inclusion, studies needed to investigate the association of TWCC with mortality or a composite endpoint that included mortality in patients with PAD. Studies were excluded when the primary focus was carotid artery disease, aortic aneurysmal disease, intracranial vascular disease, or rheumatoid arthritis and treatment with chemotherapy or transplantation of stem cells. Secondary searching of reference lists and relevant reviews was performed. Ten studies including 8,490 patients with PAD met the inclusion criteria. All studies investigated more than 100 patients with four studies assessing more than 1,000 patients. Study quality varied with well-established risk factors of outcome such as age, smoking, diabetes, and the ankle brachial index being adjusted for inconsistently. The study populations were also disparate. Few studies reported relative risk and 95% confidence intervals for the association of TWCC with mortality or MAE. TWCC was positively and significantly associated with death alone in four of five studies investigating 3,387 patients. TWCC was positively and significantly associated with MAE in five of six studies investigating a total of 6,846 patients. Current evidence suggests a positive association of TWCC with mortality and MAEs in patients with PAD. Further well-designed prospective studies are required with high-quality analysis and more complete reporting of outcomes.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2009
Abstract: An animal model commonly used to investigate pathways and potential therapeutic interventions relevant to abdominal aortic aneurysm (AAA) involves subcutaneous infusion of angiotensin II within the apolipoprotein E deficient mouse. The aim of this study was to investigate genes differentially expressed in aneurysms forming within this mouse model in order to assess the relevance of this model to human AAA. Using microarrays we identified genes relevant to aneurysm formation within apolipoprotein E deficient mice. Firstly we investigated genes differentially expressed in the aneurysm prone segment of the suprarenal aorta in these mice. Secondly we investigated genes that were differentially expressed in the aortas of mice developing aneurysms relative to those that did not develop aneurysms in response to angiotensin II infusion. Our findings suggest that a host of inflammation and extracellular matrix remodelling pathways are upregulated within the aorta in mice developing aneurysms. Kyoto Encyclopedia of Genes and Genome categories enriched in the aortas of mice with aneurysms included cytokine-cytokine receptor interaction, leukocyte transendothelial migration, natural killer cell mediated cytotoxicity and hematopoietic cell lineage. Genes associated with extracellular matrix remodelling, such as a range of matrix metalloproteinases were also differentially expressed in relation to aneurysm formation. This study is the first report describing whole genome expression arrays in the apolipoprotein E deficient mice in relation to aneurysm formation. The findings suggest that the pathways believed to be critical in human AAA are also relevant to aneurysm formation in this mouse model. The findings therefore support the value of this model to investigate interventions and mechanisms of human AAA.
Publisher: Humana Press
Date: 28-12-2009
DOI: 10.1007/978-1-60761-585-9_12
Abstract: The reasons why certain vaccine adjuvants and/or delivery systems are more or less effective at inducing immune responses or promoting the preferential induction of particular types of response are unknown. While vaccine antigen discovery has benefited from a systematic approach, our limited understanding of the interactions of adjuvants with cells of the immune system has h ered rational adjuvant discovery and handicapped the development of new and more effective vaccines. It is well accepted that the component parts of the immune system do not work in isolation and their interactions occur in distinct and specialised micro- and macro-anatomical locations. Consequently, significant obstacles to the systematic investigation of adjuvant effects have been the complexity of the physiological environments that adjuvants interact with and the difficulty in directly investigating these interactions dynamically in vivo. Here we describe some of the immunological and microscopical techniques that have enabled the analysis of the immune cells and their interactions, in vivo, in real time. It is only by performing such detailed and fundamental studies in vivo that we can fully understand the cellular and molecular interactions that control the immune response. These types of systematic analyses of the events involved in adjuvant action are a prerequisite if we are truly to design, build and target vaccines effectively.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.ATHEROSCLEROSIS.2013.12.017
Abstract: Abdominal aortic aneurysm (AAA) represents a common cause of morbidity and mortality in elderly populations but the mechanisms involved in AAA formation remain incompletely understood. Previous human studies have focused on biopsies obtained from the center of the AAA however it is likely that pathological changes also occur in relatively normal appearing aorta away from the site of main dilatation. The aim of this study was to assess the gene expression profile of biopsies obtained from the neck of human AAAs. We performed a microarray study of aortic neck specimens obtained from 14 patients with AAA and 8 control aortic specimens obtained from organ donors. Two-fold differentially expressed genes were identified with correction for multiple testing. Mechanisms represented by differentially expressed genes were identified using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Some of the differentially expressed genes were validated by quantitative real-time PCR (qPCR) and immunohistochemistry. We identified 1047 differentially expressed genes in AAA necks. The KEGG analysis revealed marked upregulation of genes related to immunity. These pathways included cytokine-cytokine receptor interaction (P = 8.67*10(-12)), chemokine signaling pathway (P = 5.76*10(-07)), and antigen processing and presentation (P = 4.00*10(-04)). Ex les of differentially expressed genes validated by qPCR included the T-cells marker CD44 (2.16-fold upregulated, P = 0.008) and the B-cells marker CD19 (3.14-fold upregulated, P = 0.029). The presence of B-cells in AAA necks was confirmed by immunohistochemistry. The role of immunity in AAA is controversial. This study suggests that immune pathways are also upregulated within the undilated aorta proximal to an AAA.
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S0264-410X(97)80002-3
Abstract: Cynomolgus monkeys (Macaca fascicularis) were immunized by intravaginal administration of live recombinant Streptococcus gordonii. The vaccine strains of S. gordonii expressed the V3 domain of the gpl20 of human immunodeficiency virus type 1 (HIV-1), and the E7 protein of human papillomavirus type 16 (HPV 16). Multiple inocula of recombinant bacteria were used, since S. gordonii could persist for no longer than 3 days in the monkey vagina. Vaginal immunization was found to induce a local and systemic immune response specific for the heterologous antigen expressed by the bacteria. This antigen-specific immune response consisted of vaginal IgA, serum IgG, and a T-cell proliferative response measured on PBMCs. Vaginal IgG and serum IgA were not detected.
Publisher: Wiley
Date: 10-2014
Abstract: Abdominal aortic aneurysm (AAA) is an important cause of mortality in the elderly. Mouse models are widely used to investigate AAA pathogenesis but their suitability for biomarker discovery is unexplored. We conducted a three-phase study. Phase 1: Aortas from angiotensin-II-infused apolipoprotein E deficient (ApoE(-/-) ) mice with and without AAA were assessed via iTRAQ and analyzed in silico to identify potential circulating markers. Microarray data from ApoE(-/-) mice and human patients were analyzed in parallel. Phase 2: Putative markers were compared between datasets to shortlist common candidates. Phase 3: The relationship of two shortlisted markers and AAA presence was assessed. iTRAQ identified eight proteins with biomarker potential. Microarray data identified 72 and 96 potential biomarkers from ApoE(-/-) mice and human patients, respectively. All three datasets suggested apolipoprotein C1 (ApoC1) as a marker for AAA microarray data identified matrix metalloproteinase 9 (MMP9) as a second potential marker. Plasma ApoC1 and MMP9 concentrations positively correlated with AAA diameter in ApoE(-/-) mice. ApoC1 may be a novel biomarker for AAA.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 27-09-2007
Abstract: Statins possess anti-inflammatory effects that may contribute to their ability to slow atherogenesis, whereas nitric oxide (NO) also influences inflammatory cell adhesion. This study aimed to determine whether a novel NO-donating pravastatin derivative, NCX 6550 [(1S-[1alpha(betaS*,deltaS*),2alpha,6alpha,8beta-(R*),8a alpha]]-1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid 4-(nitrooxy)butyl ester)], has greater anti-inflammatory properties compared with pravastatin in normal and atherosclerotic apolipoprotein E receptor knockout (ApoE-/-) mice. C57BL/6 and ApoE-/- mice were administered pravastatin (40 mg/kg), NCX 6550 (48.5 mg/kg), or vehicle orally for 5 days. Ex vivo studies assessed splenocyte adhesion to arterial segments and splenocyte reactive oxygen species (ROS) generation. NCX 6550 significantly reduced splenocyte adhesion to artery segments in both C57BL/6 (8.8 +/- 1.9% versus 16.6 +/- 6.7% adhesion P < 0.05) and ApoE-/- mice (9.3 +/- 2.9% versus 23.4 +/- 4.6% adhesion P < 0.05) concomitant with an inhibition of endothelial intercellular adhesion molecule-1 expression. NCX 6550 also significantly reduced phorbol 12-myristate 13-acetate-induced ROS production that was enhanced in isolated ApoE-/- splenocytes. Conversely, pravastatin had no significant effects on adhesion in normal or ApoE-/- mice but reduced the enhanced ROS production from ApoE-/- splenocytes. In separate groups of ApoE-/- mice, NCX 6550 significantly enhanced endothelium-dependent relaxation to carbachol in aortic segments precon-tracted with phenylephrine (-logEC(50), 6.37 +/- 0.37) compared with both vehicle-treated (-logEC50, 5.81 +/- 0.15 P < 0.001) and pravastatin-treated (-logEC50, 5.57 +/- 0.45 P < 0.05) mice. NCX 6550 also significantly reduced plasma monocyte chemoattractant protein-1 levels (648.8 pg/ml) compared with both vehicle (1191.1 pg/ml P < 0.001) and pravastatin (847 +/- 71.0 pg/ml P < 0.05) treatment. These data show that NCX 6550 exerts superior anti-inflammatory actions compared with pravastatin, possibly through NO-related mechanisms.
Publisher: Elsevier BV
Date: 07-2012
Publisher: Wiley
Date: 06-01-2015
DOI: 10.1111/IMM.12394
Publisher: Elsevier BV
Date: 02-2010
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.JVS.2007.04.031
Abstract: This article reviews the association between bone and artery disease, with particular relevance to progenitor cells. The review was based on insight gained by analysis of previous publications and on-going work by the authors. A large number of studies have demonstrated a correlation between bone pathology, particularly osteoporosis, and atherosclerosis. In this review we highlight the particular aspect of bone marrow progenitor cells in the bone-artery link. Progenitor cells, primarily those believed to give rise to endothelial cells, have been inversely correlated with atherosclerosis severity and risk factors. Therapeutic approaches aimed at manipulating progenitor cells in revascularization and vascular repair have demonstrated some promising results. Subtypes of progenitor cells have also been linked with vascular pathology, however, and further studies are required to assess relative beneficial and pathologic effects of bone marrow-derived progenitors. Further understanding of the link between bone and artery pathophysiology is likely to be of significant value in developing new therapies for vascular disease.
Publisher: Public Library of Science (PLoS)
Date: 12-10-2007
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
DOI: 10.1161/ATVBAHA.115.306945
Abstract: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein–kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated. AAA was induced in apolipoprotein E–deficient mice via infusion of angiotensin II (1.0 μg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II–induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II–induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330 5 μg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9. B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.
Publisher: Informa UK Limited
Date: 17-02-2019
DOI: 10.1080/08916934.2019.1605356
Abstract: Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are autoimmune mediated diseases triggered by group A streptococcal (GAS) infections. Molecular mimicry between GAS M-proteins and host tissue proteins has been proposed as the mechanism that initiates autoreactive immune responses in ARF/RHD. However, the in idual role of antibodies and T-cells specific for GAS M-proteins in the pathogenesis of autoimmune carditis remains under-explored. The current study investigated the role of antibodies and T-cells in the development of carditis in the Lewis rat autoimmune valvultis (RAV) model by transferring serum and/or splenic T-cells from rats previously injected with GAS recombinant M5 protein. Here we report that serum antibodies alone and serum plus in vitro expanded rM5-specific T-cells from hyperimmune rats were capable of transferring carditis to naïve syngeneic animals. Moreover, the rats that received combined serum and T-cells developed more severe carditis. Recipient rats developed mitral valvulitis and myocarditis and showed prolongation of P-R intervals in electrocardiography. GAS M5 protein-specific IgG reactivity and T-cell recall response were also demonstrated in recipient rats indicating long-term persistence of antibodies and T-cells following transfer. The results suggest that both anti-GAS M5 antibodies and T-cells have differential propensity to induce autoimmune mediated carditis in syngeneic rats following transfer. The results highlight that antibodies and effector T-cells generated by GAS M protein injection can also independently home into cardiac tissue to cross-react with tissue proteins causing autoimmune mediated immunopathology.
Publisher: Springer Science and Business Media LLC
Date: 12-2010
DOI: 10.1007/S10557-010-6262-8
Abstract: Currently there is no effective drug therapy for abdominal aortic aneurysm (AAA). The aim of this study was to assess the ability of simvastatin to inhibit aortic dilatation in two mouse models. AAAs were induced in two mice strains predisposed to atherosclerosis. Firstly, 11 weeks old male apolipoprotein E deficient (ApoE(-/-)) mice were given vehicle control (n = 27) or simvastatin (50 mg/kg/d, n = 27) prior to being infused with angiotensin II (1 μg/kg/min) subcutaneously for 4 weeks. Secondly, 9 weeks old male low-density lipoprotein receptor deficient (LDLR(-/-)) mice were fed a high fat diet, then given vehicle control (n = 17) or simvastatin (50 mg/kg/d, n = 18) and from 14 to 18 weeks of age infused with angiotensin II. Subsequently aortas were harvested, maximum suprarenal aortic diameter measured, aortic arch atheroma assessed by sudan IV staining and blood extracted to measure serum lipids. In the LDLR(-/-) mice the suprarenal aortic diameter was also measured by ultrasound prior to aortic harvesting. In ApoE(-/-) mice suprarenal aortic diameters were modestly smaller in animals receiving simvastatin without significant change despite reduction in macrophage infiltration. Aortic arch atheroma was substantially reduced in LDLR(-/-) mice receiving simvastatin with borderline significant reduction in suprarenal aortic diameters. Simvastatin did not favourably modify serum lipids in either mouse model. In this study involving two mouse models of AAA, simvastatin had limited efficacy in restricting aortic dilatation but substantial ability to reduce atheroma progression.
Publisher: Oxford University Press (OUP)
Date: 12-2007
Publisher: American Society for Microbiology
Date: 10-2014
DOI: 10.1128/IAI.01880-14
Abstract: Burkholderia pseudomallei , the etiological agent for melioidosis, is an important cause of community-acquired sepsis in northern Australia and northeast Thailand. Due to the rapid dissemination of disease in acute melioidosis, we hypothesized that dendritic cells (DC) could act as a vehicle for dissemination of B. pseudomallei . Therefore, this study investigated the effect of B. pseudomallei infection on DC migration capacity and whether migration of DC enabled transportation of B. pseudomallei from the site of infection. B. pseudomallei stimulated significantly increased migration of bone marrow-derived DC (BMDC), both in vitro and in vivo , compared to uninfected BMDC. Furthermore, migration of BMDC enabled significantly increased in vitro trafficking of B. pseudomallei and in vivo dissemination of B. pseudomallei to secondary lymphoid organs and lungs of C57BL/6 mice. DC within the footpad infection site of C57BL/6 mice also internalized B. pseudomallei and facilitated dissemination. Although DC have previously been shown to kill intracellular B. pseudomallei in vitro , the findings of this study demonstrate that B. pseudomallei -infected DC facilitate the systemic spread of this pathogen.
Publisher: Frontiers Media SA
Date: 04-11-2014
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.TUBE.2016.12.002
Abstract: Type 2 diabetes (T2D) is one of the major risk factors for tuberculosis (TB). In this study, a diet induced murine model of T2D (DIMT2D) was developed and characterized in the context of metabolic, biochemical and histopathological features following diet intervention. Mycobacterial susceptibility was investigated using Mycobacterium fortuitum as a surrogate. Phagocytic capability of alveolar macrophages and resident peritoneal macrophages were determined by in vitro assays using mycolic acid coated beads and M. fortuitum. Results demonstrated that bacillary loads were significantly higher in liver, spleen, and lungs of diabetic mice compared to controls. Higher inflammatory lesions and impaired cytokine kinetics (TNF-α, MCP-1, IL-12, IFN-γ) were also observed in diabetic mice. Macrophages isolated from diabetic mice had lower uptake of mycolic acid coated beads, reduced bacterial internalization and killing and altered cytokine responses (TNF-α, IL-6, MCP-1). This model will be useful to further investigate different facets of host-pathogen interactions in TB-T2D.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.AJPATH.2012.04.015
Abstract: There are currently no acceptable treatments to limit progression of abdominal aortic aneurysm (AAA). Increased serum concentrations of high-density lipoprotein (HDL) are associated with reduced risk of developing an AAA. The present study aimed to assess the effects of fenofibrate on aortic dilatation in a mouse model of AAA. Male low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice were maintained on a high-fat diet for 3 weeks followed by 6 weeks of oral administration of vehicle or fenofibrate. From 14 to 18 weeks of age, all mice were infused with angiotensin II (AngII). At 18 weeks of age, blood and aortas were collected for assessment of serum lipoproteins, aortic pathology, aortic Akt1 and endothelial nitric oxide synthase (eNOS) activities, immune cell infiltration, eNOS and inducible NOS (iNOS) expression, sphingosine 1 phosphate (S1P) receptor status, and apoptosis. Mice receiving fenofibrate had reduced suprarenal aortic diameter, reduced aortic arch Sudan IV staining, higher serum HDL levels, increased serum S1P concentrations, and increased aortic Akt1 and eNOS activities compared with control mice. Macrophages, T lymphocytes, and apoptotic cells were less evident and eNOS, iNOS, and S1P receptors 1 and 3 were up-regulated in aortas from mice receiving fenofibrate. The present findings suggest that fenofibrate antagonizes AngII-induced AAA and atherosclerosis by up-regulating serum HDL and S1P levels, with associated activation of NO-producing enzymes and reduction of aortic inflammation.
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0264-410X(97)00026-1
Abstract: There is a need to develop vaccines to control the spread of sexually transmitted diseases (STDs). Novel immunization strategies that elicit a mucosal immune response in the genital tract, may show improved protection by preventing or at least limiting entry of the pathogenic micro-organism. However, it has proven difficult to obtain a local immune response in the vaginal mucosa. Our approach is based on the use of recombinant bacteria capable of colonizing mucosal surfaces as live vaccine vectors. The human commensal Streptococcus gordonii, engineered to express the E7 protein of human papillomavirus type 16, was used for intravaginal immunization of mice. A single inoculum of recombinant bacteria was sufficient to establish colonization of the murine vagina and therefore induce papillomavirus-specific vaginal IgA and serum IgG. Evidence that mucosal colonization with recombinant commensal bacteria can induce a local immune response in the female genital tract represents a significant step toward the development of new vaccines against STDs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
DOI: 10.1161/ATVBAHA.112.301006
Abstract: We aimed to determine the effect of mechanistic target of rapamycin inhibitor everolimus on abdominal aortic aneurysm within the angiotensin II (A2)-infused apolipoprotein E–deficient mouse model. Abdominal aortic aneurysm was induced via subcutaneous infusion of A2. Flow cytometry demonstrated increased circulating and aortic C-C chemokine receptor 2 (CCR2) monocytes during A2 infusion. The number of CCR2 monocytes present within the aorta was positively correlated with suprarenal aortic diameter. Simultaneous infusion of everolimus via a second subcutaneous osmotic micropump inhibited A2-induced aortic dilatation. Using flow cytometry and Western blot analysis, decreased aortic dilatation was associated with reduced development of CCR2 bone marrow monocytes, fewer numbers of circulating CCR2 monocytes, and lower aortic CCR2 concentration. In vitro, everolimus inhibited A2-stimulated production of interferon (IFN)-γ and IFNγ-induced CCR2 expression in apolipoprotein E–deficient mouse bone marrow monocytes. Further, everolimus diminished IFNγ/lipopolysaccharide-stimulated M1 polarization in apolipoprotein E–deficient mouse bone marrow monocyte–differentiated macrophages. Systemic administration of everolimus limits aortic aneurysm in the A2-infused apolipoprotein E–deficient mouse model via suppressed development of bone marrow CCR2 monocytes and reduced egress of these cells into the circulation.
Publisher: Springer Science and Business Media LLC
Date: 28-05-1997
Abstract: An expression system based on the Staphylococcus aureus protein A gene (spa) was developed to allow the production and export of proteins in Lactobacillus. Plasmid shuttle vectors were constructed that carried the eZZ gene, a synthetic gene based on the Protein A gene (spa) but lacking the carboxy-terminal membrane-anchoring region. A gene fusion was created between the eZZ gene and the VD4 region of a chlamydial major outer-membrane protein gene. Expression studies demonstrated the recognition of the spa regulatory signals by several Lactobacillus, with the recombinant protein being expressed (from 0.1 microgram of EZZVD4 fusion protein per ml in L. plantarum up to 10 micrograms of EZZ protein per ml in L. fermentum) and exported (levels up to 20% in L. fermentum) in several Lactobacillus strains.
Publisher: Portland Press Ltd.
Date: 11-12-2014
DOI: 10.1042/CS20130425
Abstract: AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1–3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1–3 in AAA by qRT-PCR (quantitative reverse transcription–PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14–4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76–2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37–12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.MICINF.2014.12.007
Abstract: Melioidosis sepsis, caused by Burkholderia pseudomallei, is associated with high mortality due to an overwhelming inflammatory response. Plasmacytoid dendritic cells (pDC) are potent producers of type I interferons (IFN). This study investigated whether pDC and type I IFN play a role during the early stages of B. pseudomallei infection. Human and murine pDC internalised and killed B. pseudomallei as efficiently as murine conventional DC (cDC). pDC derived from B. pseudomallei-susceptible (BALB/c) mice demonstrated poor intracellular killing and increased IFN-alpha compared to pDC derived from B. pseudomallei-resistant (C57BL/6) mice. This is the first evidence of pDC bactericidal activity against B. pseudomallei infection.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Elsevier BV
Date: 02-2009
Publisher: Elsevier
Date: 1997
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.VACCINE.2005.08.080
Abstract: Although DNA vaccines appear to be efficient at inducing strong cellular immune responses, a number of questions remain regarding their ability to induce humoral immunity. The essential components for generating an antibody response include B and T cell recognition of antigen, subsequent activation, clonal expansion of each lymphocyte type and migration of T cells into B cell follicles to provide help, all leading to germinal centre formation and antibody production. We have employed a double adoptive transfer system based on ovalbumin (OVA)-specific CD4+ DO11.10 T cells and hen egg lysozyme (HEL)-specific MD4 B cells to assess all of these parameters in the context of DNA vaccination in vivo. We find that vaccination with DNA constructs expressing an OVA-HEL gene fusion (encoding contiguous T and B cell epitopes) can induce T cell activation, clonal expansion and migration into B cell follicles accompanied by B cell activation, blastogenesis, expansion and antibody production. These findings show that DNA vaccination can induce all of the components required for humoral immunity and also provide a system for in depth analysis of factors that influence the development of antibody responses. Such strategies may facilitate the rational design of vaccines capable of inducing effective humoral immunity.
Publisher: The Company of Biologists
Date: 11-07-2016
DOI: 10.1242/BIO.016790
Abstract: The persistent rise in global incidence of type 2 diabetes (T2D) continues to have significant public health and economic implications. The availability of relevant animal models of T2D is critical to elucidating the complexity of the pathogenic mechanisms underlying this disease and the implications this has on susceptibility to T2D complications. Whilst many high-fat diet-induced rodent models of obesity and diabetes exist, growing appreciation of the contribution of high glycaemic index diets on the development of hyperglycaemia and insulin resistance highlight the requirement for animal models that more closely represent global dietary patterns reflective of modern society. To that end, we sought to develop and validate a murine model of T2D based on consumption of an energy-dense diet containing moderate levels of fat and a high glycaemic index to better reflect the aetiopathogenesis of T2D. Male C57BL/6 mice were fed an energy-dense (ED) diet and the development of pathological features used in the clinical diagnosis of T2D was assessed over a 30-week period. Compared with control mice, 87% of mice fed an ED diet developed pathognomonic signs of T2D including glucose intolerance, hyperglycaemia, glycosylated haemoglobin (HbA1c) and glycosuria within 30 weeks. Furthermore, dyslipidaemia, chronic inflammation, alterations in circulating leucocytes and renal impairment were also evident in ED diet-fed mice compared with mice receiving standard rodent chow. Longitudinal profiling of metabolic and biochemical parameters provide support of an aetiologically and clinically relevant model of T2D that will serve as a valuable tool for mechanistic and therapeutic studies investigating the pathogenic complications of T2D.
Publisher: Springer Science and Business Media LLC
Date: 10-2007
DOI: 10.1007/S00011-007-7017-2
Abstract: The induction of an adaptive immune response is an essential step in the generation of long-lasting, protective immunity to pathogens. Many studies over the last few decades have identified the cell populations involved in the generation of antigen-specific immunity and elucidated the role of many important molecules. However, because of the low precursor frequency of antigen-specific cells, the immune system must be highly dynamic, surveying most sites of the body. Recent studies have, therefore, begun to examine how the cells of the immune system interact in vivo during the induction of an immune response, identifying new and important roles for certain molecules and revealing how previously unrecognised alterations in cell-cell interactions can have significant implications for the resulting immune response. Here we review some of these recent studies that provide a valuable insight into the mechanisms involved in the induction of immunity.
Publisher: Rockefeller University Press
Date: 31-05-2005
DOI: 10.1084/JEM.20050203
Abstract: The behavior of antigen-specific CD4+ T lymphocytes during initial exposure to antigen probably influences their decision to become primed or tolerized, but this has not been examined directly in vivo. We have therefore tracked such cells in real time, in situ during the induction of oral priming versus oral tolerance. There were marked contrasts with respect to rate and type of movement and clustering between naive T cells and those exposed to antigen in immunogenic or tolerogenic forms. However, the major difference when comparing tolerized and primed T cells was that the latter formed larger and longer-lived clusters within mucosal and peripheral lymph nodes. This is the first comparison of the behavior of antigen-specific CD4+ T cells in situ in mucosal and systemic lymphoid tissues during the induction of priming versus tolerance in a physiologically relevant model in vivo.
Publisher: SAGE Publications
Date: 27-02-2018
Abstract: Both activation of monocytes and increased serum fatty acid binding protein-4 (FABP4) occur in diabetes and are associated with increased atherosclerosis. The oxidized lipid, 9-hydroxyoctadecadienoic acid (9-HODE) increases FABP4 in macrophages, and is a ligand for G protein-coupled receptor 132 (GPR132). We investigated the involvement of GPR132 in mediating the 9-, 13-HODE stimulation of FABP4 secretion, and whether GPR132 expression is increased in monocytes from patients with type 2 diabetes. The effects of siRNA silencing of GPR132 gene and of the PPAR-γ antagonist T0070907 were studied in THP-1 cells. Serum levels of FABP4 and other adipokines were measured in patients with diabetes, and monocyte subpopulations were analyzed using flow cytometry. GPR132 mRNA was quantified in isolated CD14 + cells. 9-HODE and 13-HODE increased FABP4 expression in THP-1 monocytes and macrophages, and also increased GPR132 expression. Silencing of GPR132 did not influence the increase in FABP4 with 9-HODE, 13-HODE, or rosiglitazone (ROSI). By contrast, T0070907 inhibited the effect of all three ligands on FABP4 expression. Diabetic subjects had increased serum FABP4, and activated monocytes. They also expressed higher levels of GPR132 mRNA in CD14 + cells. We conclude that GPR132 is an independent monocyte activation marker in diabetes, but does not contribute to PPAR-γ-mediated induction of FABP4 by HODEs.
Publisher: Oxford University Press (OUP)
Date: 24-09-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
DOI: 10.1161/ATVBAHA.116.308723
Abstract: Sclerostin (SOST) has been identified as an important regulator of bone formation however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human s les, a mouse model, and in vitro investigations. SOST protein was downregulated in human and mouse AA s les compared with controls. Transgenic introduction of human SOST in apolipoprotein E–deficient ( ApoE −/− ) mice ( SOST Tg . ApoE −/− ) and administration of recombinant mouse Sost inhibited angiotensin II–induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOST Tg . ApoE −/− mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOST Tg . ApoE −/− mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/β-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOST Tg . ApoE −/− mice. SOST expression was downregulated and the wingless-type mouse mammary virus integration site/β-catenin pathway was activated in human AA s les. The cytosine–phosphate–guanine islands in the SOST gene promoter showed significantly higher methylation in human AA s les compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.
Publisher: Informa UK Limited
Date: 25-08-2016
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.TUBE.2019.02.005
Abstract: Diabetes is one of the major co-morbidities contributing to the high global burden of tuberculosis (TB). The increased susceptibility of in iduals with type 2 diabetes (T2D) to TB is multifactorial and may influence the efficacy of vaccines. This study was undertaken to determine the early immune responses that occur following infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG) in a diet-induced murine model of T2D. The phagocytic capabilities of alveolar (AM) and resident peritoneal macrophages (RPM) were assessed using ex vivo assays. Compared to macrophages from non-diabetic mice, macrophages from diabetic animals showed decreased BCG uptake and killing and inflammatory cytokine production (TNF-α, MCP-1, IL-6, IL-1β). In vivo susceptibility to BCG was determined following intravenous infection and diabetic mice showed a trend towards increased mortality, higher bacterial burden in the lung, liver and spleen and increased inflammatory lesions compared to controls. Differences between tissue cytokines were observed as early as one day post-infection and by days 14 and 35, lung and liver TNF-α and IFN-γ levels were decreased in diabetic mice compared to controls. These results suggest that early dysregulated immune responses may influence the susceptibility of T2D mice to BCG infection.
Publisher: Oxford University Press (OUP)
Date: 09-12-2017
Abstract: Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection. Both antibody and T-cell responses against immunodominant GAS virulence factors, including M protein, cross-react with host tissue proteins, triggering an inflammatory response leading to permanent heart damage. However, in some ARF/RHD-endemic regions, throat carriage of GAS is low. Because Streptococcus dysgalactiae subspecies equisimilis organisms, also known as β-hemolytic group C streptococci and group G streptococci (GGS), also express M protein, we postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Using a model initially developed to investigate the uniquely human disease of ARF/RHD, we have discovered that GGS causes interleukin 17A/interferon γ-induced myocarditis and valvulitis, hallmarks of ARF/RHD. Remarkably the histological, immunological, and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS- and GAS-exposed animals, providing additional evidence that GGS can induce and/or exacerbate ARF/RHD.
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.YJMCC.2011.06.002
Abstract: Acquired cardiovascular diseases such as coronary heart disease, peripheral artery disease and related vascular problems contribute to more than one-third of worldwide morbidity and mortality. In many instances, particularly in the under developed world, cardiovascular diseases are diagnosed at a late stage limiting the scope for improving outcomes. A range of therapies already exist for established cardiovascular disease, although there is significant interest in further understanding disease pathogenesis in order to improve diagnosis and achieve primary and secondary therapeutic goals. The urocortins are a group of recently defined peptide members of the corticotrophin-releasing factor family. Previous pre-clinical work and human association studies suggest that urocortins have potential to exert some beneficial and other detrimental effects on the heart and major blood vessels. More current evidence however favours beneficial effects of urocortins, for ex le these peptides have been shown to inhibit production of reactive oxygen species and vascular cell apoptosis, and thus may have potential to antagonise the progression of cardiovascular disease. This review summarises published data on the potential role of urocortins in cardiovascular disease.
Publisher: American Society for Microbiology
Date: 05-2004
DOI: 10.1128/IAI.72.5.2753-2761.2004
Abstract: The mucosal and cellular responses of mice were studied, following mucosal-route administration of recombinant Lactococcus lactis expressing tetanus toxin fragment C (TTFC), which is a known immunogen protective against tetanus. A TTFC-specific T-cell response with a mixed profile of T-helper (Th) subset-associated cytokines was elicited in the intestine, with a Th2 bias characteristic of a mucosal response. These results correlated with the humoral response, where equivalent titers of anti-TTFC immunoglobulin G1 (IgG1) and IgG2a in serum were accompanied by an elevated IgA-specific response at more than one mucosal site. The route of vaccination had an important role in determining the immune response phenotype, as evidenced by the fact that an IgG1-biased subclass profile was obtained when lactococci were administered parenterally. Stimulation of splenic or mesenteric lymph node cells with lactococci resulted in their proliferation and the secretion of gamma interferon via antigen-specific and innate immune mechanisms. The data therefore provide further evidence of the potential of recombinant lactococcal vaccines for inducing systemic and mucosal immune responses.
Publisher: Wiley
Date: 21-10-2014
DOI: 10.1007/S11745-014-3954-Z
Abstract: Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARγ and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP-1 monocytes and adherent THP-1 cells were compared with other C18 fatty acids, LA and α-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9-HODE (p < 0.01, 30 μM) and 13 HODE (p < 0.01, 30 μM), and the equivalent cell viability was also decreased (p < 0.001). Both 9-HODE and 13-HODE (but not LA or ALA) markedly increased caspase-3/7 activity (p < 0.001) in both monocytes and adherent THP-1 cells, with 9-HODE the more potent. In addition, 9-HODE and 13-HODE both increased Annexin-V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARγ agonist rosiglitazone (1 μM), but the effect of HODEs was replicated with apoptosis-inducer c tothecin (10 μM). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPARγ antagonist T0070907 further increased apoptosis, suggestive of the PPARγ-regulated apoptotic effects induced by 9-HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9-HODE and 13-HODE are potent--and specific--regulators of apoptosis in THP-1 cells. Their action is PPARγ-dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis.
Publisher: Oxford University Press (OUP)
Date: 16-10-2019
DOI: 10.1002/JLB.4MA0919-096RR
Abstract: The role of group A streptococcal and Streptococcus dysgalactiae subspecies equisimilis M-protein specific Abs and T-cells in endothelial cell activation was investigated using cultured rat aortic endothelial cells, and in a rat model of autoimmune valvulitis. Heat inactivated serum and mononuclear cells from streptococcal M-protein immunized rats independently induced upregulation of the endothelial cell adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in cultured cells. We also observed T-cell migration across endothelial cell monolayers incubated with serum from M-protein-immunized rats. Furthermore, we observed VCAM-1 and ICAM-1 expression in the myocardium of rats injected with M-protein compared to control animals. These observations support the contention that initial interactions between streptococcal M-protein specific Abs and/or T-cells with the heart endothelium lead to endothelial cell activation followed by transmigration of M-protein specific T-cells into heart tissue leading to an inflammatory process that leads to carditis in rheumatic fever and rheumatic heart disease.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41598-019-51892-5
Abstract: Tuberculosis remains the world’s leading cause of death from an infectious agent, and is a serious health problem in Papua New Guinea (PNG) with an estimated 36,000 new cases each year. This study describes the genetic ersity of Mycobacterium tuberculosis among tuberculosis patients in the Balimo/Bamu region in the Middle Fly District of Western Province in PNG, and investigates rif icin resistance-associated mutations. Archived Ziehl-Neelsen-stained sputum smears were used to conduct microbead-based spoligotyping and assess genotypic resistance. Among the 162 s les included, 80 (49.4%) generated spoligotyping patterns (n = 23), belonging predominantly to the L2 Lineage (44%) and the L4 Lineage (30%). This is consistent with what has been found in other PNG regions geographically distant from Middle Fly District of Western Province, but is different from neighbouring South-East Asian countries. Rif icin resistance was identified in 7.8% of the successfully sequenced s les, with all resistant s les belonging to the L2/Beijing Lineage. A high prevalence of mixed L2/L4 profiles was suggestive of polyclonal infection in the region, although this would need to be confirmed. The method described here could be a game-changer in resource-limited countries where large numbers of archived smear slides could be used for retrospective (and prospective) studies of M. tuberculosis genetic epidemiology.
Publisher: Informa UK Limited
Date: 19-08-2016
Publisher: American Association for the Advancement of Science (AAAS)
Date: 29-09-2006
Abstract: The coreceptor cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is pivotal in regulating the threshold of signals during T cell activation, although the underlying mechanism is still not fully understood. Using in vitro migration assays and in vivo two-photon laser scanning microscopy, we showed that CTLA-4 increases T cell motility and overrides the T cell receptor (TCR)–induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells. This event led to reduced contact periods between T cells and antigen-presenting cells that in turn decreased cytokine production and proliferation. These results suggest a fundamentally different model of reverse stop signaling, by which CTLA-4 modulates the threshold for T cell activation and protects against autoimmunity.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2016
DOI: 10.1038/SREP35190
Abstract: Angiogenesis and inflammation are implicated in aortic aneurysm and atherosclerosis and regulated by angiopoietin-2 (Angpt2). The effect of Angpt2 administration on experimental aortic aneurysm and atherosclerosis was examined. Six-month-old male apolipoprotein E deficient (ApoE −/− ) mice were infused with angiotensin II (AngII) and administered subcutaneous human Fc-protein (control) or recombinant Angpt2 (rAngpt2) over 14 days. Administration of rAngpt2 significantly inhibited AngII-induced aortic dilatation and rupture of the suprarenal aorta (SRA), and development of atherosclerosis within the aortic arch. These effects were blood pressure and plasma lipoprotein independent and associated with Tie2 activation and down-regulation of monocyte chemotactic protein-1 (MCP-1) within the SRA. Plasma concentrations of MCP-1 and interleukin-6 were significantly lower in mice receiving rAngpt2. Immunostaining for the monocyte/macrophage marker MOMA-2 and the angiogenesis marker CD31 within the SRA were less in mice receiving rAngpt2 than controls. The percentage of inflammatory (Ly6C hi ) monocytes within the bone marrow was increased while that in peripheral blood was decreased by rAngpt2 administration. In conclusion, administration of rAngpt2 attenuated angiotensin II-induced aortic aneurysm and atherosclerosis in ApoE −/− mice associated with reduced aortic inflammation and angiogenesis. Up-regulation of Angpt2 may have potential therapeutic value in patients with aortic aneurysm and atherosclerosis.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Catherine Rush.