{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T04:41:14Z","timestamp":1792298474072,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013218","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000}}],"reference-count":115,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R15AI178654"],"award-info":[{"award-number":["1R15AI178654"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["23AIREA1051360"],"award-info":[{"award-number":["23AIREA1051360"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007875","name":"Tulane University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007875","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>West Nile Virus (WNV), a mosquito-borne neurotropic flavivirus, is a major cause of viral encephalitis in the United States, posing a continuous threat to public health. Unfortunately, no vaccine or specific therapeutic intervention is available against WNV infection. Previous studies, including ours, demonstrated that interleukin-17A (IL-17A) signaling promotes the cytotoxicity of CD8<jats:sup>+<\/jats:sup> 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 (<jats:italic>Il17rc<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>) mice were more susceptible to WNV infection with a higher viral load in the brain than wild-type (WT) control mice. The number of infiltrating WNV-specific CD8<jats:sup>+<\/jats:sup> T cells and the expression levels of cytotoxicity mediators, such as perforin, in the T cells in the brain of <jats:italic>Il17rc<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> mice were reduced. In addition, WNV-specific CD8<jats:sup>+<\/jats:sup> T cells from IL-17RA deficient (<jats:italic>Il17ra<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>) mice and CD8<jats:sup>+<\/jats:sup> cell-specific <jats:italic>Il17ra<\/jats:italic> conditional knockout (cre-KO) mice expressed lower levels of perforin than their counterpart controls. Moreover, supplementing mouse recombinant IL-17A <jats:italic>ex vivo<\/jats:italic> increased the perforin production in WNV-specific CD8<jats:sup>+<\/jats:sup> T cells from the WT mice but not <jats:italic>Il17rc<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> or cre-KO mice. Interestingly, we found that IL-17A signaling activated the phosphatidylinositol-3-kinase\/mammalian target of rapamycin (PI3K-mTOR) signaling pathway in CD8<jats:sup>+<\/jats:sup> T cells, leading to increased metabolism of CD8<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> T cells, suggesting potential broader implications in stimulating immune responses to combat WNV and other intracellular infections.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013218","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T17:51:52Z","timestamp":1752083512000},"page":"e1013218","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism"],"prefix":"10.1371","volume":"21","author":[{"given":"Farzana","family":"Nazneen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biswas","family":"Neupane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shazeed-Ul","family":"Karim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongbing","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9170-2475","authenticated-orcid":true,"given":"Fengwei","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"issue":"4","key":"ppat.1013218.ref001","article-title":"Current understanding of West Nile virus clinical manifestations, immune responses, neuroinvasion, and immunotherapeutic implications","volume":"8","author":"F Bai","year":"2019","journal-title":"Pathogens"},{"issue":"9","key":"ppat.1013218.ref002","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S1473-3099(02)00368-7","article-title":"West Nile virus. 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