Date of Award
12-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
School
Biological, Environmental, and Earth Sciences
Committee Chair
Dr. Fengwei Bai
Committee Chair School
Biological, Environmental, and Earth Sciences
Committee Member 2
Dr. Alex Flynt
Committee Member 2 School
Biological, Environmental, and Earth Sciences
Committee Member 3
Dr. Hao Xu
Committee Member 3 School
Biological, Environmental, and Earth Sciences
Committee Member 4
Dr. Shahid Karim
Committee Member 4 School
Biological, Environmental, and Earth Sciences
Committee Member 5
Dr. Yan-Lin Guo
Committee Member 5 School
Biological, Environmental, and Earth Sciences
Abstract
West Nile Virus (WNV), a neurotropic flavivirus transmitted by mosquitoes, is a leading cause of viral encephalitis in the United States and remains a significant public health concern. Unfortunately, no vaccine or therapeutic intervention is available against WNV infection. Previous studies, including ours, demonstrated that interleukin-17A (IL-17A) signaling increases the cytotoxic potential of CD8+ T cells to facilitate WNV and parasite clearance; however, the molecular mechanism is not understood. IL-17 receptor C (IL-17RC) is an obligatory co-receptor with IL-17 receptor A (IL-17RA) for signaling induced by IL-17A, IL-17A/F, and IL-17F. In this study, we found that IL-17RC deficient (Il17rc-/-) mice were more susceptible to WNV infection with a higher viral load in the brain than wild-type (WT) control mice. In addition, the number of infiltrating WNV-specific CD8+ T cells and the expression levels of cytotoxicity mediator, such as perforin in the CD8+ T cells in the brain of Il17rc-/- mice were reduced. Moreover, supplementing mouse recombinant IL-17A (rIL-17A) ex vivo increased the perforin production in WNV-specific CD8+ T cells from the WT mice but not Il17rc-/- mice. Interestingly, we found that IL-17A signaling activated the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K-mTOR) signaling pathway in CD8+ T cells, leading to increased metabolism of CD8+ T cells to cope with the higher energy demand for WNV clearance in the brain. In summary, our findings reveal a novel IL-17A-PI3K-mTOR signaling axis in promoting the effector functions of CD8+ T cells, suggesting potential broader implications in stimulating immune responses to combat WNV and other intracellular infections.
ORCID ID
0000-0002-8142-7342
Copyright
Farzana Nazneen, 2024
Recommended Citation
Nazneen, Farzana, "Elucidating the Mechanism of Interleukin-17A Signaling in the Pathogenesis of West Nile Virus" (2024). Dissertations. 2305.
https://aquila.usm.edu/dissertations/2305
Included in
Biology Commons, Cell Biology Commons, Medical Immunology Commons, Medical Microbiology Commons, Virology Commons