Date of Award

Spring 5-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Committee Chair

Fengwei Bai

Committee Chair Department

Biological Sciences

Committee Member 2

Mohamed O. Elasri

Committee Member 2 Department

Biological Sciences

Committee Member 3

Faqing Huang

Committee Member 3 Department

Chemistry and Biochemistry

Committee Member 4

Yanlin Guo

Committee Member 4 Department

Biological Sciences

Committee Member 5

Shahid Karim

Committee Member 5 Department

Biological Sciences

Abstract

West Nile virus (WNV) is a neurotropic flavivirus of significant public health importance for which no therapeutics and vaccine are currently available. Interleukin-17A (IL-17A) is an inflammatory cytokine that regulates diverse immune functions, while its role is unclear in host’s immune response to WNV. Furthermore, CD8+ T cells are crucial components of immunity and play a vital role in recovery from WNV infection. Here, we report a previously unrecognized function of IL-17A in regulating CD8+ T cell cytotoxicity. We show that WNV induces the expression of IL-17A in both mouse splenocytes and human peripheral blood mononuclear cells cultured in vitro, and in plasma of WNV-infected mice and humans. In a mouse model of WNV infection, we demonstrate that IL-17A deficient mice (Il17a-/-) are more susceptible to WNV and develop a higher viral burden compared to wild-type (WT) mice. Interestingly, the CD8+ T cells isolated from WNV-infected Il17a-/- mice are less cytotoxic and express lower levels of cytotoxic mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Moreover, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 post-infection, significantly reduces viral burden and increases survival, suggesting a therapeutic potential of IL-17A. In conclusion, we demonstrate a novel function of IL-17A in promoting CD8+ T cell cytotoxicity against WNV infection, which may have broad implications in other microbial infections and cancers.

ORCID ID

0000-0003-1929-3870

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