ORCID Profile
0000-0002-8796-4755
Current Organisation
University of York
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Publisher: Public Library of Science (PLoS)
Date: 22-09-2016
Publisher: Springer Science and Business Media LLC
Date: 20-12-2016
Publisher: American Society for Clinical Investigation
Date: 04-2010
DOI: 10.1172/JCI41281
Publisher: Frontiers Media SA
Date: 27-03-2018
Publisher: Wiley
Date: 04-02-2008
Publisher: Hindawi Limited
Date: 25-08-2011
DOI: 10.1111/J.1462-5822.2011.01658.X
Abstract: Leishmania parasites are well adapted to initiate infection, resist the onslaught of innate immunity and achieve a state of long-lived persistence. In recent years, the tools available to study these interactions have developed enormously and have become much more widely available. Confocal microscopy, live cell imaging, whole animal imaging and intra-vital 2-photon now complement and extend the classical light and electron microscopical techniques. Coupled with approaches to generate transgenic parasites that express imaging friendly reporter proteins, these tools are making the full breadth of the life cycle accessible to imaging studies. New insights into the life history of these highly successful parasites are emerging with increasing frequency, and often with startling clarity and visual drama. In this short review, we focus on how this new generation of imaging-based research tools has augmented our understanding of the complex interplay that occurs between Leishmania and the cells that it infects in mammalian hosts.
Publisher: Wiley
Date: 30-12-2009
Publisher: Springer Science and Business Media LLC
Date: 17-12-2015
Publisher: Public Library of Science (PLoS)
Date: 30-03-2012
Publisher: Elsevier BV
Date: 09-2013
Publisher: Public Library of Science (PLoS)
Date: 12-03-2010
Publisher: The American Association of Immunologists
Date: 12-2009
Abstract: Dendritic cells (DC) licensed by the interaction between pathogen products and pattern recognition receptors can activate naive T cells to undergo Ag-dependent proliferation and cytokine production. In contrast, DC induced to mature by trans-acting inflammatory stimuli are believed to only be capable of supporting Ag-dependent proliferative responses. In this study, we show that uninfected DC matured as a consequence of Leishmania-induced inflammation induce CD8+ T cells to proliferate in the absence of their cognate Ag. We separated splenic DC from Leishmania donovani-infected mice into those that contained parasites and had been activated to induce IL-12p40, from those that had undergone only partial maturation, measured by increased CD86 expression in the absence of IL-12p40 induction. We then showed that these partially matured DC could induce exogenous peptide-independent proliferation of OT-I and F5 CD8+ TCR transgenic T cells, as well as polyclonal CD8+ T cells. Proliferation of OT-I cells was significantly inhibited in vitro and in vivo by anti-CD86 mAb but not by anti-CD80 mAb and could also be inhibited by cyclosporine A. Proliferating OT-I cells did not produce IFN-γ, even when re-exposed to mature DC. However, these primed OT-I cells subsequently produced effector cytokines, not just on exposure to their cognate peptide but, more importantly, to weak exogenous TCR agonists that otherwise failed to induce IFN-γ. We further showed that OT-I cells undergoing locally driven proliferation to another pathogen, Streptococcus pneumoniae, rapidly seeded other lymphoid tissues, suggesting that CD8+ T cells primed in this way may play a role in rapidly countering pathogen dissemination.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2015
DOI: 10.1007/S00204-015-1575-9
Abstract: Many substances are hepatotoxic due to their ability to cause intrahepatic cholestasis. Therefore, there is a high demand for in vitro systems for the identification of cholestatic properties of new compounds. Primary hepatocytes cultivated in collagen sandwich cultures are known to establish bile canaliculi which enclose secreted biliary components. Cholestatic compounds are mainly known to inhibit bile excretion dynamics, but may also alter canalicular volume, or hepatocellular morphology. So far, techniques to assess time-resolved morphological changes of bile canaliculi in sandwich cultures are not available. In this study, we developed an automated system that quantifies dynamics of bile canaliculi recorded in conventional time-lapse image sequences. We validated the hepatocyte sandwich culture system as an appropriate model to study bile canaliculi in vitro by showing structural similarity measured as bile canaliculi length per hepatocyte to that observed in vivo. Moreover, bile canalicular excretion kinetics of CMFDA (5-chloromethylfluorescein diacetate) in sandwich cultures resembled closely the kinetics observed in vivo. The developed quantification technique enabled the quantification of dynamic changes in in idual bile canaliculi. With this technique, we were able to clearly distinguish between sandwich cultures supplemented with dexamethasone and insulin from control cultures. In conclusion, the automated quantification system offers the possibility to systematically study the causal relationship between disturbed bile canalicular dynamics and cholestasis.
Publisher: American Society for Clinical Investigation
Date: 15-11-2021
DOI: 10.1172/JCI142765
Publisher: The American Association of Immunologists
Date: 06-2020
Abstract: Despite extensive mapping of long noncoding RNAs in immune cells, their function in vivo remains poorly understood. In this study, we identify over 100 long noncoding RNAs that are differentially expressed within 24 h of Th1 cell activation. Among those, we show that suppression of Malat1 is a hallmark of CD4+ T cell activation, but its complete deletion results in more potent immune responses to infection. This is because Malat1−/− Th1 and Th2 cells express lower levels of the immunosuppressive cytokine IL-10. In vivo, the reduced CD4+ T cell IL-10 expression in Malat1−/−mice underpins enhanced immunity and pathogen clearance in experimental visceral leishmaniasis (Leishmania donovani) but more severe disease in a model of malaria (Plasmodium chabaudi chabaudi AS). Mechanistically, Malat1 regulates IL-10 through enhancing expression of Maf, a key transcriptional regulator of IL-10. Maf expression correlates with Malat1 in single Ag-specific Th cells from P. chabaudi chabaudi AS–infected mice and is downregulated in Malat1−/− Th1 and Th2 cells. The Malat1 RNA is responsible for these effects, as antisense oligonucleotide-mediated inhibition of Malat1 also suppresses Maf and IL-10 levels. Our results reveal that through promoting expression of the Maf/IL-10 axis in effector Th cells, Malat1 is a nonredundant regulator of mammalian immunity.
Publisher: American Society for Microbiology
Date: 04-2017
DOI: 10.1128/IAI.01021-16
Abstract: Salmonella enterica serovar Typhi is a human-restricted Gram-negative bacterial pathogen responsible for causing an estimated 27 million cases of typhoid fever annually, leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by the activity of glycosyltransferase ( gtr ) operons acquired by horizontal gene transfer. Here we investigate the role of two gtr operons that we identified in the S . Typhi genome. Strains were engineered to express specific gtr operons. Full chemical analysis of the O-antigens of these strains identified gtr -dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered the expression of this glucosylating gtr operon uniform in the population. In contrast, the expression of the acetylating gtrC gene is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism, and thus, this modification may contribute to persistence in a host. In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modifications should be taken into consideration when assessing responses to vaccines, especially O-antigen-based vaccines, and that the Salmonella gtr repertoire may confound the protective efficacy of broad-ranging Salmonella lipopolysaccharide conjugate vaccines.
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: American Society for Microbiology
Date: 03-2011
DOI: 10.1128/IAI.00633-10
Abstract: Optimal hepatic resistance to Leishmania donovani in mice requires the coordinated effort of a variety of leukocyte populations that together induce activation of local macrophages to a leishmanicidal state. Although nitric oxide and reactive oxygen intermediates are potent leishmanicidal effector molecules operating in the acquired phase of immunity, there have long been suggestions that other mechanisms of leishmanicidal activity exist. We recently discovered that Irf-7 regulates a novel innate leishmanicidal response in resident splenic macrophages that line the marginal zone. Here, we tested whether this mechanism also operates in Kupffer cells, the resident macrophage population of the liver and the major target for hepatic infection by L. donovani . Comparing the Kupffer cell responses in situ in B6 and B6. Irf-7 −/− mice, we found no evidence that Irf-7 affected amastigote uptake or early survival. However, we did find that Irf-7 -deficient mice had impaired acquired resistance to hepatic L. donovani infection. This phenotype was attributable to a reduction in the capacity of hepatic CD4 + T cells, NK cells, and NKT cells to produce gamma interferon (IFN-γ) and also to defective induction of NOS2 in infected Kupffer cells. Our data therefore add interferon regulatory factor 7 (IRF-7) to the growing list of interferon regulatory factors that have effects on downstream events in the acquired cellular immune response to nonviral pathogens.
Publisher: Elsevier BV
Date: 10-2016
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: Springer Berlin Heidelberg
Date: 2010
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 12-2020
Publisher: Frontiers Media SA
Date: 2013
Publisher: Public Library of Science (PLoS)
Date: 26-07-2012
Publisher: Elsevier BV
Date: 08-2008
Publisher: Public Library of Science (PLoS)
Date: 12-03-2010
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2023
DOI: 10.1101/2023.02.03.526940
Abstract: Many parasites of significant public health importance assume skin residency without causing overt pathlogy. How immune and stromal cells respond to such “cryptic” infections and how exposure to UVB alters such responses in poorly understood. We combined scRNA-seq, spatial transcriptomics and inferential network analysis to address these questions in a model of cryptic skin infection by Leishmania donovani . In infected C57BL/6 mice, p-selectin and CXCL12 interactions dominate intercellular communication between leucocytes, fibroblast and endothelial cells, but effector T cell function remains muted. Following UVB exposure, increased numbers of IFNγ + CD4 + Th1 cells and NK cells enter the skin, communicating with stromal cells via CCL5-CCR5 and LFA-1-ICAM1/2. However, spatial mapping indicated that Th1 cells and macrophages occupied distinct niches after UVB exposure, likely limiting effector function. Our data provide the first holistic view of the immune landscape during cryptic L. donovani infection and demonstrate how UVB exposure fundamentally reshapes this response.
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
Publisher: Elsevier BV
Date: 07-2011
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
No related grants have been discovered for Paul Kaye.