Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Phillip Scott

Abstract

Cutaneous leishmaniasis is a significant global health concern with more than 350 million people worldwide at risk of infection. One of the most interesting and confounding aspects of leishmaniasis is the broad spectrum of disease severity seen in patients. The role of CD8 T cells during leishmaniasis has been controversial, but is currently thought to entail the production of IFN-&gamma to polarize CD4 T cells towards a protective Th1 type immune response. However, analysis of CD8 T cells in human lesions does not demonstrate significant IFN-&gamma production by these cells. Additionally, CD8 T cells taken from patient lesions are responsive to a number of other pathogens, indicating significant infiltration of bystander CD8 T cells into the lesions during natural infection. Given this, we hypothesized that a patient's immunologic history may have a profound effect on the disease progression of Leishmania infection. To test this we examined the functionality of CD8 T cells, both antigen specific and bystander cells generated in response to other pathogens, at the site of infection with L. major. We show that CD8 T cells in the skin adopt a cytotoxic phenotype and express high levels of gzmB but little IFN-&gamma. To evaluate the potential role of bystander cells in the lesions during L. major infection, we utilized two distinct infection scenarios: a prior viral or bacterial infection that is cleared before challenge with L. major and a direct coinfection with a virus at the peak of lesion formation. In both cases, bystander cells exacerbated the disease course of L. major. In the case of a previous infection, this immunopathology was not associated with any change in parasite control. Whereas, in the case of direct coinfection the immunopathology was associated with an increased parasite burden in both the skin and DLN. Strikingly, regardless of the timing of the heterologous infection, the immunopathology was mediated in a CD8 T cell, NKG2D dependent manner. This work identifies NKG2D and its ligands as potential therapeutic targets in leishmaniasis and has broad implications for the potential role of this pathway in other infections where excessive tissue damage and immunopathology are observed.

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