{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:10:15Z","timestamp":1785161415462,"version":"3.55.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"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. Microbiol."],"abstract":"<jats:p>Powassan virus (POWV) is a tick-borne flavivirus that causes neurotropic disease in humans. POWV causes fatal encephalitis and meningitis in 10% of human cases and long-term neurological sequelae in 50% of surviving patients. While innate antiviral responses have been extensively studied in mosquito-borne flavivirus infections, they remain less well characterized in the context of tick-borne flaviviruses. In this study, we investigated the role of interferon \u03b1\/\u03b2 receptor in the pathogenesis of POWV infection <jats:italic>in vivo<\/jats:italic>. Herein, we showed that unlike wild-type (WT) mice, interferon \u03b1\/\u03b2 receptor-deficient (<jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) mice were highly susceptible to POWV and rapidly succumbed to infection. Low inoculum dosage resulted in 100% mortality rate in <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice early after infection. Higher levels of viremia accompanied by increased serum levels of proinflammatory cytokines and chemokines were observed in <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. Further, we detected significantly higher virus levels in the peripheral tissues including spleen, liver and kidney in <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice compared to WT mice. Subsequent analyses revealed marked pathology and elevated inflammatory responses in the peripheral organs of <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. Additionally, <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice showed a stunted immune response in the spleen with significantly decreased numbers of B cells, monocytes, and neutrophils. While WT mice exhibited increased splenic accumulation of Ly6C<jats:sup>+<\/jats:sup> cells, this recruitment was markedly impaired in <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. Notably, viral load quantification and immunofluorescence analysis showed no significant difference in brain viral load between WT and <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice; however, <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice displayed elevated inflammatory response in the brain. These data suggest that the rapid mortality observed in <jats:italic>Ifnar<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice is due to uncontrolled virus dissemination and excessive inflammation in the periphery rather than brain infection. Collectively, our data reveal that the type-I interferon response restricts viral tropism and pathogenesis of POWV in mice.<\/jats:p>","DOI":"10.3389\/fmicb.2025.1678861","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T05:36:03Z","timestamp":1759815363000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Interferon-alpha\/beta receptor deficiency enhances susceptibility to Powassan virus infection in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Amany","family":"Elsharkawy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinonye","family":"Dim","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":[[2025,10,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1275823","DOI":"10.3389\/fcimb.2023.1275823","article-title":"The critical role of interleukin-6 in protection against neurotropic flavivirus infection","volume":"13","author":"Auroni","year":"2023","journal-title":"Front. 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