Elucidating the Mechanism of Interleukin-17A Signaling in the Pathogenesis of West Nile Virus

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.