ORCID Profile
0000-0003-2260-0026
Current Organisations
University of Melbourne
,
Caterham School
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Infectious Agents | Biological Mathematics | Microbiology | Medical Parasitology | Host-Parasite Interactions |
Expanding Knowledge in the Biological Sciences | Infectious Diseases | Expanding Knowledge in the Mathematical Sciences | Expanding Knowledge in the Medical and Health Sciences
Publisher: American Society for Microbiology
Date: 08-2007
DOI: 10.1128/IAI.00404-07
Abstract: Melioidosis is an emerging disease of humans in Southeast Asia and tropical Australia. The bacterium causing this disease, Burkholderia pseudomallei , is also considered a bioterrorism agent, and as yet there is no licensed vaccine for preventing B. pseudomallei infection. In this study, we evaluated selected proteins (LolC, PotF, and OppA) of the ATP-binding cassette systems of B. pseudomallei as candidate vaccine antigens. Nonmembrane regions of the B. pseudomallei proteins were expressed and purified from Escherichia coli and then evaluated as vaccine candidates in an established mouse model of B. pseudomallei infection. When delivered with the monophosphoryl lipid A-trehalose dicorynomycolate adjuvant, the proteins stimulated antigen-specific humoral and cellular immune responses. Immunization with LolC or PotF protein domains afforded significant protection against a subsequent challenge with B. pseudomallei . The most promising vaccine candidate, LolC, provided a greater level of protection when it was administered with immune-stimulating complexes complexed with CpG oligodeoxynucleotide 10103. Immunization with LolC also protected against a subsequent challenge with a heterologous strain of B. pseudomallei , demonstrating the potential utility of this protein as a vaccine antigen for melioidosis.
Publisher: Wiley
Date: 22-01-2007
DOI: 10.1111/J.1365-3024.2006.00930.X
Abstract: Tumour necrosis factor (TNF) plays important roles in the pathogenesis of severe malaria, as well as in the generation of immune responses against malaria parasites. However, far less is known about the role of the closely related TNF family member lymphotoxin alpha (LTalpha) during malaria. We have used mice deficient in either TNF or LTalpha, as well as chimeric mice generated using donor bone marrow from these animals, to study the roles of these cytokines following Plasmodium chabaudi chabaudi AS infection. TNF and LTalpha were not required for the resolution of P. chabaudi chabaudi AS blood-stage infection. However, LTalpha, but not TNF, was necessary for early IFNgamma production and the regulation of IFNgamma production later in infection. A similar delay to that found for IFNgamma production was also observed for TNF production in LTalpha-deficient mice, compared with control mice. These results identify ergent roles for TNF and LTalpha in the regulation of host immune responses during P. chabaudi chabaudi AS infection.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2016
Publisher: Cold Spring Harbor Laboratory
Date: 13-09-2016
DOI: 10.1101/074971
Abstract: Differentiation of naïve CD4 + T cells into functionally distinct T helper subsets is crucial for the orchestration of immune responses. Due to multiple levels of heterogeneity and multiple overlapping transcriptional programs in differentiating T cell populations, this process has remained a challenge for systematic dissection in vivo . By using single-cell RNA transcriptomics and computational modelling of temporal mixtures, we reconstructed the developmental trajectories of Th1 and Tfh cell populations during Plasmodium infection in mice at single-cell resolution. These cell fates emerged from a common, highly proliferative and metabolically active precursor. Moreover, by tracking clonality from T cell receptor sequences, we infer that ancestors derived from the same naïve CD4 + T cell can concurrently populate both Th1 and Tfh subsets. We further found that precursor T cells were coached towards a Th1 but not a Tfh fate by monocytes/macrophages. The integrated genomic and computational approach we describe is applicable for analysis of any cellular system characterized by differentiation towards multiple fates. Using single-cell RNA sequencing and a novel unsupervised computational approach, we resolve the developmental trajectories of two CD4 + T cell fates in vivo , and show that uncommitted T cells are externally influenced towards one fate by inflammatory monocytes.
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1038/NM.3446
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-481-4_23
Abstract: The term "severe malaria" refers to a wide spectrum of syndromes in Plasmodium-infected humans including cerebral malaria (CM), respiratory distress, severe anemia, liver dysfunction, and hypoglycemia. Mouse models have been employed to further our understanding of the pathology and immune responses that occur during Plasmodium infection. Evidence of brain, liver, lung, and spleen pathology, as well as anemia and tissue-sequestration of parasites, has been reported in various strains of inbred mice. While no single mouse model mimics all the various clinical manifestations of severe malaria in humans, here we describe a detailed protocol for Plasmodium berghei ANKA infection of C57BL/6J mice. For many years, this model has been referred to as "experimental cerebral malaria," but in fact recapitulates many of the symptoms and pathologies observed in most severe malaria syndromes.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.IJPARA.2017.05.009
Abstract: The artemisinins are the first-line therapy for severe and uncomplicated malaria, since they cause rapid declines in parasitemia after treatment. Despite this, in vivo mechanisms underlying this rapid decline remain poorly characterised. The overall decline in parasitemia is the net effect of drug inhibition of parasites and host clearance, which competes against any ongoing parasite proliferation. Separating these mechanisms in vivo was not possible through measurements of total parasitemia alone. Therefore, we employed an adoptive transfer approach in which C57BL/6J mice were transfused with Plasmodium berghei ANKA strain-infected, fluorescent red blood cells, and subsequently drug-treated. This approach allowed us to distinguish between the initial drug-treated generation of parasites (Gen
Publisher: Wiley
Date: 17-08-2017
DOI: 10.1111/PIM.12455
Abstract: Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2020
DOI: 10.1101/2020.05.18.101048
Abstract: The most advanced malaria vaccine only has approximately 30% efficacy in target populations, and avenues to improve next generation vaccines need to be identified. Functional antibodies are key effectors of both vaccine induced and naturally acquired immunity, with induction driven by T-follicular helper cells (TfH) CD4+ T cells. We assessed circulating TfH (cTfH) responses and functional antibody production in human volunteers experimentally infected with Plasmodium falciparum . Longitudinal single-cell RNA-sequencing of cTfH revealed peak transcriptional activation and clonal expansion of major cTfH subsets occurred at day 8 following infection and a population structure of cTfH capturing phenotypical subsets of Th1- and Th2-like cells. Among 40 volunteers, infection resulted in the emergence of activated ICOS+ cTfH cells. During peak infection, activation was restricted to Th2-like cTfH cells, while Th1-like cTfH cell activation occurred one week after treatment. To link cTfH activation to antibody induction, we assessed the magnitude and function of anti-malarial IgM and IgG after infection. The functional breadth and magnitude of parasite-specific antibodies was positively associated with Th2-cTfH activation. In contrast, Th1-cTfH activation was associated with the induction of plasma cells, which we have previously shown have a detrimental role in germinal cell formation and antibody development. Thus, we identified that during P. falciparum malaria infection in humans, the activation of Th2-cTfH but not other subsets correlates with the development of functional antibodies required for protective immunity. Data for the first time identify a specific cellular response that can be targeted by future malaria vaccines to improve antibody induction.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2015
DOI: 10.1038/SREP09412
Abstract: The best correlate of malaria severity in human Plasmodium falciparum ( Pf ) infection is the total parasite load. Pf- infected humans could control parasite loads by two mechanisms, either decreasing parasite multiplication, or increasing parasite clearance. However, few studies have directly measured these two mechanisms in vivo . Here, we have directly quantified host clearance of parasites during Plasmodium infection in mice. We transferred labelled red blood cells (RBCs) from Plasmodium infected donors into uninfected and infected recipients and tracked the fate of donor parasites by frequent blood s ling. We then applied age-based mathematical models to characterise parasite clearance in the recipient mice. Our analyses revealed an increased clearance of parasites in infected animals, particularly parasites of a younger developmental stage. However, the major decrease in parasite multiplication in infected mice was not mediated by increased clearance alone, but was accompanied by a significant reduction in the susceptibility of RBCs to parasitisation.
Publisher: Springer Science and Business Media LLC
Date: 10-2001
DOI: 10.1038/35101607
Publisher: The American Association of Immunologists
Date: 12-2008
DOI: 10.4049/JIMMUNOL.181.11.7458
Abstract: Studies in experimental cerebral malaria (ECM) in mice have identified T cells and TNF family members as critical mediators of pathology. In this study we report a role for LIGHT-lymphotoxin β Receptor (LTβR) signaling in the development of ECM and control of parasite growth. Specific blockade of LIGHT-LTβR, but not LIGHT-herpesvirus entry mediator interactions, abrogated the accumulation of parasites and the recruitment of pathogenic CD8+ T cells and monocytes to the brain during infection without affecting early activation of CD4+ T cells, CD8+ T cells, or NK cells. Importantly, blockade of LIGHT-LTβR signaling caused the expansion of splenic monocytes and an overall enhanced capacity to remove and process Ag during infection, as well as reduced systemic cytokine levels when control mice displayed severe ECM symptoms. In summary, we have discovered a novel pathogenic role for LIGHT and LTβR in ECM, identifying this TNF family receptor-ligand interaction as an important immune regulator during experimental malaria.
Publisher: American Society for Microbiology
Date: 14-07-2023
Abstract: Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute Plasmodium infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation in vivo using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation in vivo . Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.
Publisher: Wiley
Date: 05-06-2019
DOI: 10.1111/IMCB.12272
Abstract: The ability of circulating CD4
Publisher: American Society for Microbiology
Date: 09-2006
DOI: 10.1128/IAI.02046-05
Abstract: Burkholderia mallei is a gram-negative bacterium which causes the potentially fatal disease glanders in humans however, there is little information concerning cell-mediated immunity to this pathogen. The role of gamma interferon (IFN-γ) during B. mallei infection was investigated using a disease model in which infected BALB/c mice normally die between 40 and 60 days postinfection. IFN-γ knockout mice infected with B. mallei died within 2 to 3 days after infection, and there was uncontrolled bacterial replication in several organs, demonstrating the essential role of IFN-γ in the innate immune response to this pathogen. Increased levels of IFN-γ, interleukin-6 (IL-6), and monocyte chemoattractant protein 1 were detected in the sera of immunocompetent mice in response to infection, and splenic mRNA expression of IFN-γ, IL-6, IL-12p35, and IL-27 was elevated 24 h postinfection. The effects of IL-18, IL-27, and IL-12 on stimulation of the rapid IFN-γ production were investigated in vitro by analyzing IFN-γ production in the presence of heat-killed B. mallei . IL-12 was essential for IFN-γ production in vitro IL-18 was also involved in induction of IFN-γ, but IL-27 was not required for IFN-γ production in response to heat-killed B. mallei . The main cellular sources of IFN-γ were identified in vitro as NK cells, CD8 + T cells, and TCRγδ T cells. Our data show that B. mallei is susceptible to cell-mediated immune responses which promote expression of type 1 cytokines. This suggests that development of effective vaccines against glanders should target the production of IFN-γ.
Publisher: Microbiology Society
Date: 08-2004
Abstract: Melioidosis is a severe infectious disease of animals and humans caused by the Gram-negative intracellular pathogen Burkholderia pseudomallei . An Inv/Mxi-Spa-like type III protein secretion apparatus, encoded by the B. pseudomallei bsa locus, facilitates bacterial invasion of epithelial cells, escape from endocytic vesicles and intracellular survival. This study investigated the role of the Bsa type III secretion system in the pathogenesis of melioidosis in murine models. B. pseudomallei bipD mutants, lacking a component of the translocation apparatus, were found to be significantly attenuated following intraperitoneal or intranasal challenge of BALB/c mice. Furthermore, a bipD mutant was attenuated in C57BL/6 IL-12 p40 −/− mice, which are highly susceptible to B. pseudomallei infection. Mutation of bipD impaired bacterial replication in the liver and spleen of BALB/c mice in the early stages of infection. B. pseudomallei mutants lacking either the type III secreted guanine nucleotide exchange factor BopE or the putative effectors BopA or BopB exhibited varying degrees of attenuation, with mutations in bopA and bopB causing a significant delay in median time to death. This indicates that bsa -encoded type III secreted proteins may act in concert to determine the outcome of B. pseudomallei infection in mice. Mice inoculated with the B. pseudomallei bipD mutant were partially protected against subsequent challenge with wild-type B. pseudomallei . However, immunization of mice with purified BipD protein was not protective.
Publisher: Elsevier BV
Date: 02-2001
DOI: 10.1016/S1369-5274(00)00170-3
Abstract: Wild Escherichia coli are superbly adapted to survive in the intestines of their mammalian hosts and in the environment. E. coli K12 derivative (MG1655) encodes 4288 potential genes that provide the background genetic framework of this species. Particular E. coli clonal types encode additional chromosomal and extrachromosomal genes that facilitate the ability of E. coli to adapt to new environments. These additional genes are often clustered, have related functions (for ex le, virulence-associated genes in pathogenicity islands) and may be integrated at specific sites on the E. coli chromosome.
Publisher: American Society for Microbiology
Date: 26-10-2023
DOI: 10.1128/IAI.00317-23
Publisher: Cold Spring Harbor Laboratory
Date: 19-08-2021
DOI: 10.1101/2021.08.18.456784
Abstract: Maturation rate of malaria parasites within red blood cells (RBC) can be influenced by host nutrient status or circadian rhythm. Here, we observed in mice that systemic host inflammation, induced by lipopolysaccharide (LPS) conditioning or ongoing acute malaria infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. LPS-conditioning and acute infection both triggered substantial changes to the metabolomic composition of plasma in which parasites circulated. This altered plasma directly slowed parasite maturation in a manner that could not be rescued by supplementation, consistent with the presence of inhibitory factors. Single-cell transcriptomic assessment of mixed parasite populations, exposed to a short period of systemic host inflammation in vivo , revealed specific impairment in the transcriptional activity and translational capacity of trophozoites compared to rings or schizonts. Thus, we provide in vivo evidence of transcriptomic and phenotypic plasticity of asexual blood-stage Plasmodium parasites when exposed to systemic host inflammation.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.IJPARA.2018.05.010
Abstract: A major mechanism of host-mediated control of blood-stage Plasmodium infection is thought to be removal of parasitized red blood cells (pRBCs) from circulation by the spleen or phagocytic system. The rate of parasite removal is thought to be further increased by anti-malarial drug treatment, contributing to the effectiveness of drug therapy. It is difficult to directly compare pRBC removal rates in the presence and absence of treatment, since in the absence of treatment the removal rate of parasites is obscured by the extent of ongoing parasite proliferation. Here, we transfused a single generation of fluorescently-labelled Plasmodium berghei pRBCs into mice, and monitored both their disappearance from circulation, and their replication to produce the next generation of pRBCs. In conjunction with a new mathematical model, we directly estimated host removal of pRBCs during ongoing infection, and after drug treatment. In untreated mice, pRBCs were removed from circulation with a half-life of 15.1 h. Treatment with various doses of mefloquine/artesunate did not alter the pRBC removal rate, despite blocking parasite replication effectively. An exception was high dose artesunate, which doubled the rate of pRBC removal (half-life of 9.1 h). Phagocyte depletion using clodronate liposomes approximately halved the pRBC removal rate during untreated infection, indicating a role for phagocytes in clearance. We next assessed the importance of pRBC clearance for the decrease in the parasite multiplication rate after high dose artesunate treatment. High dose artesunate decreased parasite replication ∼46-fold compared with saline controls, with inhibition of replication contributing 23-fold of this, and increased pRBC clearance contributing only a further 2.0-fold. Thus, in our in vivo systems, drugs acted primarily by inhibiting parasite replication, with drug-induced increases in pRBC clearance making only minor contributions to overall drug effect.
Publisher: American Society for Microbiology
Date: 05-2011
DOI: 10.1128/IAI.01210-10
Abstract: Infection of C57BL/6 mice with Plasmodium berghei ANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological symptoms and mortality depend on pathogenic CD8 + T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8 + T cells accumulated in the liver following P. berghei ANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset of clinical symptoms. These data indicate that CD8 + T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both organs during P. berghei ANKA infection. Therefore, we show that P. berghei ANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized by organ-specific CD8 + T cell-mediated pathology.
Publisher: Wiley
Date: 11-08-2018
DOI: 10.1111/IMR.12697
Abstract: Malaria infection continues to be a major health problem worldwide and drug resistance in the major human parasite species, Plasmodium falciparum, is increasing in South East Asia. Control measures including novel drugs and vaccines are in development, and contributions to the rational design and optimal usage of these interventions are urgently needed. Infection involves the complex interaction of parasite dynamics, host immunity, and drug effects. The long life cycle (48 hours in the common human species) and synchronized replication cycle of the parasite population present significant challenges to modeling the dynamics of Plasmodium infection. Coupled with these, variation in immune recognition and drug action at different life cycle stages leads to further complexity. We review the development and progress of "within-host" models of Plasmodium infection, and how these have been applied to understanding and interpreting human infection and animal models of infection.
Publisher: American Society for Microbiology
Date: 12-2005
DOI: 10.1128/IAI.73.12.7996-8001.2005
Abstract: It has been proposed that long-lived memory T cells generated by vaccination or infection reside within a memory compartment that has a finite size. Consequently, in a variety of acute infection models interclonal competition has been shown to lead to attrition of preexisting memory CD8 + T cells. Contrary to expectations, therefore, we found that chronic Leishmania donovani infection of Listeria -immune mice results in heightened protection against subsequent Listeria challenge. This protection was associated with bystander expansion of Listeria -specific CD8 + T cells and a bias in these cells toward a central memory T-cell phenotype with an enhanced capacity for gamma interferon production. We propose that splenomegaly, which is characteristic of visceral leishmaniasis and other tropical infections, may help promote heterologous immunity by resetting the size of the memory compartment during chronic infection.
Publisher: American Society for Microbiology
Date: 25-02-2015
DOI: 10.1128/CVI.00051-15
Abstract: Acute lower respiratory tract infections (ALRTI) are the leading cause of global childhood mortality, with human respiratory syncytial virus (hRSV) being a major cause of viral ALRTI in young children worldwide. In sub-Saharan Africa, many young children experience severe illnesses due to hRSV or Plasmodium infection. Although the incidence of malaria in this region has decreased in recent years, there remains a significant opportunity for coinfection. Recent data show that febrile young children infected with Plasmodium are often concurrently infected with respiratory viral pathogens but are less likely to suffer from pneumonia than are non- Plasmodium -infected children. Here, we hypothesized that blood-stage Plasmodium infection modulates pulmonary inflammatory responses to a viral pathogen but does not aid its control in the lung. To test this, we established a novel coinfection model in which mice were simultaneously infected with pneumovirus of mice (PVM) (to model hRSV) and blood-stage Plasmodium chabaudi chabaudi AS ( Pc AS) parasites. We found that Pc AS infection was unaffected by coinfection with PVM. In contrast, PVM-associated weight loss, pulmonary cytokine responses, and immune cell recruitment to the airways were substantially reduced by coinfection with Pc AS. Importantly, Pc AS coinfection facilitated greater viral dissemination throughout the lung. Although Plasmodium coinfection induced low levels of systemic interleukin-10 (IL-10), this regulatory cytokine played no role in the modulation of lung inflammation or viral dissemination. Instead, we found that Plasmodium coinfection drove an early systemic beta interferon (IFN-β) response. Therefore, we propose that blood-stage Plasmodium coinfection may exacerbate viral dissemination and impair inflammation in the lung by dysregulating type I IFN-dependent responses to respiratory viruses.
Publisher: Future Medicine Ltd
Date: 08-2009
DOI: 10.2217/FMB.09.43
Abstract: Vaccination remains a crucial component of any initiative to control or eradicate malaria. With increasing reports of insecticide resistance in mosquitoes, and malaria parasite resistance to first-line drugs, it is clear that the development of an effective malaria vaccine is an urgent requirement for the improvement of global human health. This article highlights malaria vaccine research-related discoveries from 2008/9 to suggest that the time is now ripe for researchers to develop malaria vaccines that target many antigens from multiple stages of the parasite’s lifecycle. We also call for greater bidirectional information transfer between preclinical and clinical trials, to facilitate more efficient improvement of malaria vaccine candidates.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.CELL.2011.04.004
Abstract: Although a link between sickle cell disease and resistance to severe malaria is well established, the biochemical relationship between the two is unknown. Ferreira et al. (2011) show that carriers of the sickle cell mutation increase expression of the heme oxygenase-1 enzyme, which produces antioxidant molecules that may prevent severe disease symptoms.
Publisher: Oxford University Press (OUP)
Date: 12-2008
Publisher: American Physical Society (APS)
Date: 02-10-2015
Publisher: Oxford University Press (OUP)
Date: 11-2006
DOI: 10.1086/508217
Abstract: Burkholderia pseudomallei is the etiological agent of melioidosis, a serious human disease for which no vaccine is available. Immunization of susceptible BALB/c mice with the live attenuated mutant B. pseudomallei ilvI (referred to as "2D2") generated significant, although incomplete, immunity. Splenic B. pseudomallei-specific T cells, detected in immunized mice, proliferated and produced interferon-gamma in vitro in response to dead bacteria. Assessment of T cell antigen specificity indicated that subpopulations of B. pseudomallei-reactive T cells were responsive to BopE, a type III secretion system (TTSS) effector protein, and to a lesser extent to BipD, a TTSS translocator protein. Increased survival of severe combined immunodeficient mice adoptively transferred with T cells from immunized mice, compared with that of naive T cell recipients, demonstrated that immunization with 2D2 generated T cell-mediated immunity. CD4+ and CD8+ cell depletion studies demonstrated that CD4+ cells, but not CD8+ cells, mediated this protection in vivo. Thus, CD4+ T cells can mediate vaccine-induced immunity to experimental melioidosis.
Publisher: Wiley
Date: 18-07-2023
DOI: 10.1111/IMCB.12569
Publisher: Springer Science and Business Media LLC
Date: 29-10-2010
Abstract: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes. An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P -values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of 0.05 was considered statistically significant. No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found. These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2022
DOI: 10.1186/S13073-022-01075-1
Abstract: Single-cell transcriptomics (scRNA-seq) has become essential for biomedical research over the past decade, particularly in developmental biology, cancer, immunology, and neuroscience. Most commercially available scRNA-seq protocols require cells to be recovered intact and viable from tissue. This has precluded many cell types from study and largely destroys the spatial context that could otherwise inform analyses of cell identity and function. An increasing number of commercially available platforms now facilitate spatially resolved, high-dimensional assessment of gene transcription, known as ‘spatial transcriptomics’. Here, we introduce different classes of method, which either record the locations of hybridized mRNA molecules in tissue, image the positions of cells themselves prior to assessment, or employ spatial arrays of mRNA probes of pre-determined location. We review sizes of tissue area that can be assessed, their spatial resolution, and the number and types of genes that can be profiled. We discuss if tissue preservation influences choice of platform, and provide guidance on whether specific platforms may be better suited to discovery screens or hypothesis testing. Finally, we introduce bioinformatic methods for analysing spatial transcriptomic data, including pre-processing, integration with existing scRNA-seq data, and inference of cell-cell interactions. Spatial -omics methods are already improving our understanding of human tissues in research, diagnostic, and therapeutic settings. To build upon these recent advancements, we provide entry-level guidance for those seeking to employ spatial transcriptomics in their own biomedical research.
Publisher: Public Library of Science (PLoS)
Date: 23-11-2015
Publisher: Public Library of Science (PLoS)
Date: 03-11-2016
Publisher: Springer Science and Business Media LLC
Date: 16-07-2021
DOI: 10.1038/S41467-021-24570-2
Abstract: Mucosal-associated Invariant T (MAIT) cells are recognized for their antibacterial functions. The protective capacity of MAIT cells has been demonstrated in murine models of local infection, including in the lungs. Here we show that during systemic infection of mice with Francisella tularensis live vaccine strain results in evident MAIT cell expansion in the liver, lungs, kidney and spleen and peripheral blood. The responding MAIT cells manifest a polarised Th1-like MAIT-1 phenotype, including transcription factor and cytokine profile, and confer a critical role in controlling bacterial load. Post resolution of the primary infection, the expanded MAIT cells form stable memory-like MAIT-1 cell populations, suggesting a basis for vaccination. Indeed, a systemic vaccination with synthetic antigen 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil in combination with CpG adjuvant similarly boosts MAIT cells, and results in enhanced protection against both systemic and local infections with different bacteria. Our study highlights the potential utility of targeting MAIT cells to combat a range of bacterial pathogens.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 03-03-2023
DOI: 10.1101/2023.03.02.530907
Abstract: Children in malaria-endemic regions can experience multiple Plasmodium infections over a short period of time, with in vitro CD4 + T cell recall responses becoming more regulatory with increasing age and exposure. This suggests that repeated infection qualitatively changes CD4 + T cells, although the heterogeneity and dynamics of these responses await systematic analysis in vivo . Here, we examined TCR transgenic PbTII and polyclonal CD4 + T cells during Plasmodium re-infection in mice, in conjunction with scRNA-seq/TCR-seq and spatial transcriptomics at near single-cell resolution. PbTII cells gave rise to multiple antigen-experienced states in different areas of the spleen after primary infection and antimalarial treatment, including ongoing GC responses and T-cell zone memory. Upon re-infection, Th1-memory PbTII cells initiated a rapid effector response prior to proliferating, while GC Tfh cells of the same antigen specificity were entirely refractory within the same organ. Transcriptome dynamic modelling and network analysis of Th1 recall revealed a biphasic wave of RNA processing that firstly preceded immune effector transcription, and later accompanied cellular proliferation. Importantly, Th1 recall constituted a partial facsimile of primary Th1 responses, with no unique genes amongst the small subset of those upregulated upon re-infection. Finally, we noted a similar spectrum of antigen-experienced states and recall dynamics by polyclonal CD4 + T cells with erse TCRs. Therefore, during re-infection with Plasmodium , persisting GC Tfh cells remained unaltered transcriptionally, Tcm/Tfh-like cells exhibited minimal proliferation, and Th1-memory cells displayed a rapid, proliferating IL-10-producing Tr1 response consistent with a shift towards immune-regulation. These data highlight a broad spectrum of simultaneous CD4 + T cell responses that occur in the spleen during re-infection with malaria parasites. Splenic TCR transgenic CD4 + T cells are highly heterogeneous prior to re-infection. Persisting GC Tfh cells are refractory to re-activation during re-infection. Th1-memory cells rapidly upregulate RNA processing prior to effector function and proliferation. Th1-recall is an imperfect but faithful facsimile of primary Th1 responses. A spectrum of recall states is observed in polyclonal CD4 + T cells with erse TCRs.
Publisher: The American Association of Immunologists
Date: 15-12-2017
Abstract: We describe an MHC class II (I-Ab)–restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell–mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.
Publisher: Public Library of Science (PLoS)
Date: 12-02-2016
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-03-2017
DOI: 10.1126/SCIIMMUNOL.AAL2192
Abstract: Computational modeling defines T helper cell differentiation toward multiple fates during experimental malaria.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2017
Publisher: BMJ
Date: 10-2004
Publisher: Public Library of Science (PLoS)
Date: 12-02-2016
Publisher: Wiley
Date: 13-11-2014
Abstract: Type I IFN signaling suppresses splenic T helper 1 (Th1) responses during blood-stage Plasmodium berghei ANKA (PbA) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. Interferon regulatory factor 7 (IRF7) is considered to be a master regulator of type I IFN responses. Here, we assessed IRF7 for its roles during lethal PbA infection and nonlethal Plasmodium chabaudi chabaudi AS (PcAS) infection as two distinct models of blood-stage malaria. We found that IRF7 was not essential for tissue accumulation of parasites, cerebral symptoms, or brain pathology. Using timed administration of anti-IFNAR1 mAb, we show that late IFNAR1 signaling promotes fatal disease via IRF7-independent mechanisms. Despite this, IRF7 significantly impaired early splenic Th1 responses and limited control of parasitemia during PbA infection. Finally, IRF7 also suppressed antiparasitic immunity and Th1 responses during nonlethal PcAS infection. Together, our data support a model in which IRF7 suppresses antiparasitic immunity in the spleen, while IFNAR1-mediated, but IRF7-independent, signaling contributes to pathology in the brain during experimental blood-stage malaria.
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2023
DOI: 10.1101/2023.02.23.529309
Abstract: CD4 + T cells orchestrate adaptive immunity to circulating malaria parasites yet cellular interactions and molecular mechanisms controlling Th1 and Tfh differentiation in the spleen remain to be fully defined in vivo . Here, using a murine model of CD4-dependent immunity, we tested if Slide-seqV2 , a spatial transcriptomic method with near single-cell resolution, could determine the locations of multiple CD4 + T cell subsets and potentially interacting cellular partners in the spleen during infection. Firstly, Slide-seqV2 readily mapped splenic cellular structure and microanatomical change during infection. Next, computational integration with scRNA-seq reference datasets of splenocytes, stromal cells, and specifically of polyclonal CD4 + T cells and B cells, mapped the relative locations of multiple cell-types within this dense tissue. scRNA-seq of B cells over time mapped emergence of germinal centre B cells, red pulp-located plasmablasts and atypical B cells, and uncovered a prolonged CD4 + T-cell-independent, follicular bystander B cell response marked by Sca-1 and Ly6C upregulation. scRNA-seq of activated, polyclonal CD4 + T cells revealed their similarity to our previous TCR transgenic models. Importantly, spatial analysis revealed polyclonal Th1 cells co-localised with CXCL9/10-producing monocytes in the red pulp, while polyclonal Tfh-like cells were located close to CXCL13-expressing B cell follicles, consistent with our previous CXCR3/CXCR5 competition model of Th1/Tfh bifurcation. CRISPR/Cas9 disruption of either or both CXCR3 and CXCR5 in naïve Plasmodium -specific CD4 + T cells had unexpectedly minor effects on Th1 differentiation in vivo . Instead, CXCR5 was essential for maximising clonal expansion, suggesting a role for splenic CXCL13 + cells in supporting CD4 + T cell proliferation in malaria. Thus, spatial transcriptomics at near single-cell resolution was feasible in densely packed secondary lymphoid tissue, providing multiple insights into mechanisms controlling splenic polyclonal CD4 + T cell and B cell differentiation during infection. Slide-seqV2 maps splenic microanatomy, including stromal and immune cell location. Bystander activation of all follicular B cells occurs in malaria, marked by Sca-1/Ly6C upregulation. Single naïve polyclonal CD4 + T cells differentiate mostly into Th1 and Tfh cells in malaria. Cell-cell colocalization analysis positions Th1 cells with monocytes in red pulp, and Tfh cells with Cxcl13 + B cell follicles. CXCR5, but not CXCR3, supports parasite-specific CD4 + T cell clonal expansion.
Publisher: Wiley
Date: 04-2020
DOI: 10.1111/IMCB.12336
Publisher: Oxford University Press (OUP)
Date: 15-08-2011
Publisher: Oxford University Press (OUP)
Date: 2007
DOI: 10.1086/509810
Abstract: Inhalation is an important route of infection with Burkholderia pseudomallei, the causative agent of melioidosis. In resistant C57BL/6 mice, activated neutrophils are rapidly recruited to the lungs after intranasal B. pseudomallei infection. Prevention of this response by use of the anti-Gr-1+ cell-depleting monoclonal antibody RB6-8C5 severely exacerbated disease, resulting in an acute lethal infection associated with a 1000-fold increase in lung bacterial loads within 4 days. C57BL/6 interferon (IFN)-gamma(-/-) mice were also acutely susceptible to pulmonary B. pseudomallei infection, dying within 3 days of challenge this suggests that IFN-gamma is essential for control in the lungs and precedes the protective role of neutrophils in resistance. In neutrophil-depleted mice, lung concentrations of tumor necrosis factor (TNF)-alpha, IFN-gamma, and interleukin-6 were decreased by up to 98%. Natural killer cells were the principle source of IFN-gamma, and monocytes were the principle source of TNF-alpha, suggesting that neutrophils play an important indirect role in the generation of the early cytokine environment in the lungs.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-01-2022
DOI: 10.1126/SCIIMMUNOL.ABJ0641
Abstract: A erse fibroblastic stromal cell landscape in the spleen directs tissue homeostasis and immunity.
Publisher: American Society for Microbiology
Date: 15-09-2005
Publisher: The American Association of Immunologists
Date: 15-05-2007
DOI: 10.4049/JIMMUNOL.178.10.6033
Abstract: Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection, causing significant morbidity and mortality among young children and nonimmune adults in the developing world. Although previous work on experimental CM has identified T cells as key mediators of pathology, the APCs and subsets therein required to initiate immunopathology remain unknown. In this study, we show that conventional dendritic cells but not plasmacytoid dendritic cells are required for the induction of malaria parasite-specific CD4+ T cell responses and subsequent experimental CM. These data have important implications for the development of malaria vaccines and the therapeutic management of CM.
Publisher: Oxford University Press (OUP)
Date: 02-2006
DOI: 10.1086/498983
Abstract: Antigen-specific T cells are important sources of interferon (IFN)-gamma for acquired immunity to intracellular pathogens, but they can also produce IFN- gamma directly via a "bystander" activation pathway in response to proinflammatory cytokines. We investigated the in vivo role of cytokine- versus antigen-mediated T cell activation in resistance to the pathogenic bacterium Burkholderia pseudomallei. IFN-gamma, interleukin (IL)-12, and IL-18 were essential for initial bacterial control in infected mice. B. pseudomallei infection rapidly generated a potent IFN-gamma response from natural killer (NK) cells, NK T cells, conventional T cells, and other cell types within 16 h after infection, in an IL-12- and IL-18-dependent manner. However, early T cell- and NK cell-derived IFN-gamma responses were functionally redundant in cell depletion studies, with IFN-gamma produced by other cell types, such as major histocompatibility complex class II(int) F4/80(+) macrophages being sufficient for initial resistance. In contrast, B. pseudomallei-specific CD4(+) T cells played an important role during the later stage of infection. Thus, the T cell response to primary B. pseudomallei infection is biphasic, an early cytokine-induced phase in which T cells appear to be functionally redundant for initial bacterial clearance, followed by a later antigen-induced phase in which B. pseudomallei-specific T cells, in particular CD4(+) T cells, are important for host resistance.
Publisher: Proceedings of the National Academy of Sciences
Date: 03-07-2017
Abstract: Adaptive immunity to Plasmodium falciparum takes years to develop in endemic regions, leaving young children vulnerable to high parasite burdens and severe malaria. Host innate immune responses clearly occur during infection and may control parasite numbers in nonimmune in iduals, for ex le by accelerating parasite removal from circulation. However, evidence of whether and how this occurs in vivo remains sparse. We set out to measure host removal of parasites during acute blood-stage Plasmodium infection in mice. However, rather than being removed more rapidly, parasites unexpectedly persisted in circulation. Persistence resulted from host-dependent slowing of parasite maturation. Thus Plasmodium maturation within red blood cells does not occur at a constant rate in vivo and can be influenced by the host itself.
Publisher: Public Library of Science (PLoS)
Date: 22-05-2014
Publisher: The American Association of Immunologists
Date: 15-03-2018
Abstract: CD4+ Th cell differentiation is crucial for protecting against blood-stage Plasmodium parasites, the causative agents of malaria. It has been known for decades that more than one type of Th cell develops during this infection, with early models proposing a biphasic Th1/Th2 model of differentiation. Over the past decade, a large body of research, in particular, reports over the past 2–3 y, have revealed substantial complexity in the Th differentiation program during Plasmodium infection. In this article, we review how several studies employing mouse models of malaria, and recent human studies, have redefined the process of Th differentiation, with a particular focus on Th1 and T follicular helper (Tfh) cells. We review the molecular mechanisms that have been reported to modulate Th1/Tfh differentiation, and propose a model of Th1/Tfh differentiation that accommodates observations from all recent murine and human studies.
Publisher: American Society for Microbiology
Date: 2014
DOI: 10.1128/IAI.00705-13
Abstract: Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum -infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection.
Publisher: The American Association of Immunologists
Date: 15-02-2018
Abstract: Differentiation of CD4+ Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage Plasmodium parasites, yet their influence over Th cell immunity remains unclear. In this study, we used Plasmodium-reactive TCR transgenic CD4+ T cells, termed PbTII cells, during nonlethal P. chabaudi chabaudi AS and P. yoelii 17XNL infection in mice, to examine Th cell development in vivo. We found no role for caspase1/11, stimulator of IFN genes, or mitochondrial antiviral-signaling protein, and only modest roles for MyD88 and TRIF-dependent signaling in controlling PbTII cell expansion. In contrast, IFN regulatory factor 3 (IRF3) was important for supporting PbTII expansion, promoting Th1 over T follicular helper (Tfh) differentiation, and controlling parasites during the first week of infection. IRF3 was not required for early priming by conventional dendritic cells, but was essential for promoting CXCL9 and MHC class II expression by inflammatory monocytes that supported PbTII responses in the spleen. Thereafter, IRF3-deficiency boosted Tfh responses, germinal center B cell and memory B cell development, parasite-specific Ab production, and resolution of infection. We also noted a B cell–intrinsic role for IRF3 in regulating humoral immune responses. Thus, we revealed roles for IRF3 in balancing Th1- and Tfh-dependent immunity during nonlethal infection with blood-stage Plasmodium parasites.
Publisher: American Society for Clinical Investigation
Date: 09-07-2020
Publisher: The American Association of Immunologists
Date: 06-2011
Abstract: Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8+ T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8+ T cells expressed granzyme B (GzmB). Furthermore, gzmB−/− mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4+ T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8+ T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8+ T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8+ T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8+ T cells dictates the onset of perforin/GzmB-mediated ECM.
Publisher: The American Association of Immunologists
Date: 12-2018
Abstract: The outcome of intracellular parasitic infection can be determined by the immunoregulatory activities of natural regulatory CD4+ Foxp3+ T (Treg) cells and the anti-inflammatory cytokine IL-10. These mechanisms protect tissue but can also suppress antiparasitic CD4+ T cell responses. The specific contribution of these regulatory pathways during human parasitic diseases remains unclear. In this study, we investigated the roles of Treg cells and IL-10 during experimental visceral leishmaniasis caused by Leishmania donovani infection of C57BL/6 mice. We report only a limited contribution of Treg cells in suppressing antiparasitic immunity, but important roles in delaying the development of splenic pathology and restricting leukocyte expansion. We next employed a range of cell-specific, IL-10– and IL-10R–deficient mice and found these Treg cell functions were independent of IL-10. Instead, conventional CD4+ T cells and dendritic cells were the most important cellular sources of IL-10, and the absence of IL-10 in either cell population resulted in greater control of parasite growth but also caused accelerated breakdown in splenic microarchitecture. We also found that T cells, dendritic cells, and other myeloid cells were the main IL-10–responding cells because in the absence of IL-10R expression by these cell populations, there was greater expansion of parasite-specific CD4+ T cell responses associated with improved control of parasite growth. Again, however, there was also an accelerated breakdown in splenic microarchitecture in these animals. Together, these findings identify distinct, cell-specific, immunoregulatory networks established during experimental visceral leishmaniasis that could be manipulated for clinical advantage.
Publisher: Oxford University Press (OUP)
Date: 07-2010
DOI: 10.1086/653125
Publisher: Public Library of Science (PLoS)
Date: 27-02-2019
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Publisher: The American Association of Immunologists
Date: 15-04-2014
Abstract: Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell–mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.
Publisher: Cold Spring Harbor Laboratory
Date: 03-03-2017
DOI: 10.1101/113837
Abstract: We describe an MHC II (IA b )-restricted T cell receptor (TCR) transgenic mouse line that produces CD4 + T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4 + T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, P. chabaudi AS and P. yoelii 17XNL) and human ( P . falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of antibody to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8 + T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8 + T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8 + DC (a subset of XCR1 + DC) were the major antigen presenting cell (APC) responsible for activation of both T cell subsets, though other DC also contributed to CD4 + T cell responses. Depletion of CD8 + DC at the beginning of infection prevented ECM development and impaired both Th1 and Tfh responses in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4 + T cell immunity during malaria and provides evidence that CD4 + T cell help, acting via CD40L signalling, can promote immunity or pathology to blood stage malaria largely through antigen presentation by CD8 + DC.
Publisher: Public Library of Science (PLoS)
Date: 18-02-2013
Publisher: Springer Science and Business Media LLC
Date: 10-05-2016
DOI: 10.1038/NCOMMS11514
Abstract: Although memory T cells within barrier tissues can persist as permanent residents, at least some exchange with blood. The extent to which this occurs is unclear. Here we show that memory CD4 + T cells in mouse skin are in equilibrium with the circulation at steady state. These cells are dispersed throughout the inter-follicular regions of the dermis and form clusters with antigen presenting cells around hair follicles. After infection or administration of a contact sensitizing agent, there is a sustained increase in skin CD4 + T-cell content, which is confined to the clusters, with a concomitant CCL5-dependent increase in CD4 + T-cell recruitment. Skin CCL5 is derived from CD11b + cells and CD8 + T cells, with the elimination of the latter decreasing CD4 + T-cell numbers. These results reveal a complex pattern of tissue-retention and equilibration for CD4 + memory T cells in skin, which is altered by infection and inflammation history.
Publisher: Frontiers Media SA
Date: 12-10-2017
Publisher: Wiley
Date: 05-07-2018
DOI: 10.1111/IMM.12971
Publisher: Wiley
Date: 29-11-2012
DOI: 10.1038/ICB.2011.97
Abstract: Parasitic diseases cause significant global morbidity and mortality, particularly in underdeveloped regions of the world. Malaria alone causes ~800000 deaths each year, with children and pregnant women being at highest risk. There is no licensed vaccine available for any human parasitic disease and drug resistance is compromising the efficacy of many available anti-parasitic drugs. This is driving drug discovery research on new agents with novel modes of action. Histone deacetylase (HDAC) inhibitors are being investigated as drugs for a range of diseases, including cancers and infectious diseases such as HIV/AIDS, and several parasitic diseases. This review focuses on the current state of knowledge of HDAC inhibitors targeted to the major human parasitic diseases malaria, schistosomiasis, trypanosomiasis, toxoplasmosis and leishmaniasis. Insights are provided into the unique challenges that will need to be considered if HDAC inhibitors are to be progressed towards clinical development as potential new anti-parasitic drugs.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JACI.2016.02.039
Abstract: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized. We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections. Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release. PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-α and IFN-λ production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice. Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-α production. We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.
Publisher: Rockefeller University Press
Date: 22-12-2017
DOI: 10.1084/JEM.20170298
Abstract: Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2022
DOI: 10.1101/2022.11.10.516078
Abstract: Bacterial urinary tract infections (UTIs) are both common and exhibit high recurrence rates in women. UTI healthcare costs are increasing due to the rise of multi-drug resistant (MDR) bacteria, necessitating alternative approaches for infection control. Here, we investigated whether host adaptive immune responses can influence infection outcomes. We employed a mouse model in which wild-type C57BL/6J mice were transurethrally inoculated with an MDR UTI strain of uropathogenic Escherichia coli (UPEC). Firstly, we noted that rag1 -/- C57BL/6J mice harboured larger bacterial burdens than wild-type counterparts, consistent with a role for T and/or B cells in optimal control of UTI. Consistent with this, UTI triggered in the bladders of wild-type mice early increases of myeloid cells, including CD11c hi conventional dendritic cells, suggesting possible involvement of these professional antigen-presenting cells. Importantly, germinal centre (GC) B cell responses developed by 4 weeks post-infection in bladder-draining lymph nodes of wild-type mice, and although modest in magnitude and transient in nature, could not be boosted with a second UTI. Thus, our data reveal for the first time in a mouse model, that Gram-negative bacterial UTI induces local B cell immune responses in bladder-draining lymph nodes, which could potentially serve to control infection.
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1016/S0264-410X(99)00417-X
Abstract: We have investigated the ability of the growth phase regulated promoters dps and spv, to drive expression of heterologous antigens in Salmonella vaccine strains. Reporter plasmids were constructed which directed beta-galactosidase expression from dps (pDpslacZ) or spv (pSpvlacZ) and these were introduced independently into the Salmonella typhimurium vaccine strain SL3261 (aroA(-)). beta-galactosidase expression was induced 20-fold and 100-fold when broth cultures of SL3261 (pDpslacZ) or SL3261 (pSpvlacZ) respectively, entered the stationary phase of growth. Within macrophages, beta-galactosidase expression was induced 3.5-fold with SL3261 (pDpslacZ) and 7-fold with SL3261 (pSpvlacZ). The spv and dps promoters were used to drive independent expression of the C fragment domain of tetanus toxin (TetC) from plasmids harboured in S. typhimurium SL3261. Levels of anti-TetC antibodies were significantly higher in the sera of BALB/c mice perorally inoculated with SL3261 (pSpvtetC) or SL3261 (pDpstetC) compared to unvaccinated controls. This suggests that these promoter systems may be used to drive foreign antigen expression in live oral Salmonella vaccines.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 06-2018
End Date: 12-2021
Amount: $462,710.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2012
End Date: 05-2015
Amount: $300,000.00
Funder: Australian Research Council
View Funded Activity