ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Virology
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1678861
Interferon-alpha/beta receptor deficiency enhances susceptibility to Powassan virus infection in mice
Provisionally accepted
- Georgia State University, Atlanta, United States
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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 α/β receptor in the pathogenesis of POWV infection in vivo. Herein, we showed that unlike wild-type (WT) mice, interferon α/β receptor-deficient (Ifnar-/-) mice were highly susceptible to POWV and rapidly succumbed to infection. Low inoculum dosage resulted in 100% mortality rate in Ifnar-/- mice early after infection. Higher levels of viremia accompanied by increased serum levels of proinflammatory cytokines and chemokines were observed in Ifnar-/- mice. Further, we detected significantly higher virus levels in the peripheral tissues including spleen, liver and kidney in Ifnar-/- mice compared to WT mice. Subsequent analyses revealed marked pathology and elevated inflammatory responses in the peripheral organs of Ifnar-/- mice. Additionally, Ifnar-/- 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⁺ cells, this recruitment was markedly impaired in Ifnar-/- mice. Notably, viral load quantification and immunofluorescence analysis showed no significant difference in brain viral load between WT and Ifnar-/- mice; however, Ifnar-/- mice displayed elevated inflammatory response in the brain. These data suggest that the rapid mortality observed in Ifnar-/- 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.
Keywords: Orthoflavivirus, Powassan virus, Inflammation, interferon response, Interferon-alpha/beta receptor
Received: 03 Aug 2025; Accepted: 23 Sep 2025.
Copyright: © 2025 Elsharkawy, Pathak, Dim and Kumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mukesh Kumar, mkumar8@gsu.edu
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