{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:43:37Z","timestamp":1791333817381,"version":"4.3.1"},"reference-count":95,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T00:00:00Z","timestamp":1700092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>West Nile virus (WNV) and Japanese encephalitis virus (JEV) are emerging mosquito-borne flaviviruses causing encephalitis globally. No specific drug or therapy exists to treat flavivirus-induced neurological diseases. The lack of specific therapeutics underscores an urgent need to determine the function of important host factors involved in flavivirus replication and disease progression. Interleukin-6 (IL-6) upregulation has been observed during viral infections in both mice and humans, implying that it may influence the disease outcome significantly. Herein, we investigated the function of IL-6 in the pathogenesis of neurotropic flavivirus infections. First, we examined the role of IL-6 in flavivirus-infected human neuroblastoma cells, SK-N-SH, and found that IL-6 neutralization increased the WNV or JEV replication and inhibited the expression of key cytokines. We further evaluated the role of IL-6 by infecting primary mouse cells derived from IL-6 knockout (IL-6<jats:sup>\u2212\/\u2212<\/jats:sup>) mice and wild-type (WT) mice with WNV or JEV. The results exhibited increased virus yields in the cells lacking the IL-6 gene. Next, our <jats:italic>in vivo<\/jats:italic> approach revealed that IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice had significantly higher morbidity and mortality after subcutaneous infection with the pathogenic WNV NY99 or JEV Nakayama strain compared to WT mice. The non-pathogenic WNV Eg101 strain did not cause mortality in WT mice but resulted in 60% mortality in IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice, indicating that IL-6 is required for the survival of mice after the peripheral inoculation of WNV or JEV. We also observed significantly higher viremia and brain viral load in IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice than in WT mice. Subsequently, we explored innate immune responses in WT and IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice after WNV NY99 infection. Our data demonstrated that the IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice had reduced levels of key cytokines in the serum during early infection but elevated levels of proinflammatory cytokines in the brain later, along with suppressed anti-inflammatory cytokines. In addition, mRNA expression of IFN-\u03b1 and IFN-\u03b2 was significantly lower in the infected IL-6<jats:sup>\u2212\/\u2212<\/jats:sup> mice. In conclusion, these data suggest that the lack of IL-6 exacerbates WNV or JEV infection <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> by causing an increase in virus replication and dysregulating host immune response.<\/jats:p>","DOI":"10.3389\/fcimb.2023.1275823","type":"journal-article","created":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T17:33:32Z","timestamp":1700156012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["The critical role of interleukin-6 in protection against neurotropic flavivirus infection"],"prefix":"10.3389","volume":"13","author":[{"given":"Tabassum T.","family":"Auroni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal","family":"Arora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janhavi P.","family":"Natekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany","family":"Elsharkawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukesh","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.3390\/v11020162","article-title":"Integrated MicroRNA and mRNA profiling in zika virus-infected neurons","volume":"11","author":"Azouz","year":"2019","journal-title":"Viruses"},{"key":"B2","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1365-2249.1995.tb06659.x","article-title":"The acute phase protein response in patients receiving subcutaneous IL-6","volume":"102","author":"Banks","year":"1995","journal-title":"Clin. 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