Immune Regulation during Experimental Visceral Leishmaniasis

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Author(s)
Primary Supervisor
Good, Michael
Other Supervisors
Batzloff, Michael
Engwerda, Christian
Year published
2014
Metadata
Show full item recordAbstract
Visceral Leishmaniasis (VL) is a chronic infectious disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi) responsible for significant morbidity and mortality in the developing world. Transmitted by sand fly vectors, Leishmania parasites preferentially infect host macrophages throughout the viscera. Experimental L. donovani infection in genetically susceptible mice elicits a highly organ-specific outcome that mirrors much of the immunopathology observed in human VL patients. In this context, the liver is a site of an acute, resolving infection whereas parasite persistence is established in ...
View more >Visceral Leishmaniasis (VL) is a chronic infectious disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi) responsible for significant morbidity and mortality in the developing world. Transmitted by sand fly vectors, Leishmania parasites preferentially infect host macrophages throughout the viscera. Experimental L. donovani infection in genetically susceptible mice elicits a highly organ-specific outcome that mirrors much of the immunopathology observed in human VL patients. In this context, the liver is a site of an acute, resolving infection whereas parasite persistence is established in the chronically infected spleen. Generation of an effective immune response against infection requires IFNγ- and TNF-producing CD4+ T(h1) cells. Functional impairment of this pro-inflammatory subset is noted during chronic infection. Here, we describe 3 distinct pathways by which L. donovani promotes persistence within the host via the impairment of protective Th1 responses. IL-10 is a potent immunoregulatory cytokine well known for its T cell-modulatory activity. IL-10-producing CD4+ Th1 (Tr1) cells were found to contribute to much of the dysregulation observed during chronic L. donovani infection in C57BL/6 mice. While not influencing parasite control, Foxp3+ regulatory T(reg) cells were determined to be required for the induction of Tr1 cell populations during established infection. During chronic infection, however, Treg cells appeared to restrict the expansion of pathogenic Tr1 cells.
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View more >Visceral Leishmaniasis (VL) is a chronic infectious disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi) responsible for significant morbidity and mortality in the developing world. Transmitted by sand fly vectors, Leishmania parasites preferentially infect host macrophages throughout the viscera. Experimental L. donovani infection in genetically susceptible mice elicits a highly organ-specific outcome that mirrors much of the immunopathology observed in human VL patients. In this context, the liver is a site of an acute, resolving infection whereas parasite persistence is established in the chronically infected spleen. Generation of an effective immune response against infection requires IFNγ- and TNF-producing CD4+ T(h1) cells. Functional impairment of this pro-inflammatory subset is noted during chronic infection. Here, we describe 3 distinct pathways by which L. donovani promotes persistence within the host via the impairment of protective Th1 responses. IL-10 is a potent immunoregulatory cytokine well known for its T cell-modulatory activity. IL-10-producing CD4+ Th1 (Tr1) cells were found to contribute to much of the dysregulation observed during chronic L. donovani infection in C57BL/6 mice. While not influencing parasite control, Foxp3+ regulatory T(reg) cells were determined to be required for the induction of Tr1 cell populations during established infection. During chronic infection, however, Treg cells appeared to restrict the expansion of pathogenic Tr1 cells.
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Thesis Type
Thesis (PhD Doctorate)
Degree Program
Doctor of Philosophy (PhD)
School
Institute for Glycomics
Copyright Statement
The author owns the copyright in this thesis, unless stated otherwise.
Item Access Status
Public
Subject
Biological Sciences
Medical and Health Sciences
Visceral leishmaniasis (VL)
Protozoan parasite Leishmania donovani
Protozoan parasite L. infantum (chagasi)
Experimental L. donovani infection
Sand fly vectors
Treg cells