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However, without knowledge of differences in viral burdens, it remains unclear whether NK cells are elevated due to hepatitis A virus (HAV) replication and ongoing associated injury, or if NK cell responses directly cause pathogenesis. To gain insight into how NK cells respond during the early stages of hepatitis A virus infection, we generated mice that are permissive for HAV infection in the liver but are otherwise immunocompetent. HAV readily infected the liver of these hepatocyte-specific type-I interferon receptor knockout mice (\n                      <jats:italic toggle=\"yes\">\n                        Ifnar1\n                        <jats:sup>\u0394Hep<\/jats:sup>\n                      <\/jats:italic>\n                      ), resulting in fecal virus shedding, elevated serum alanine aminotransferase levels, and immune cell infiltrates in the liver. Single-cell RNA sequencing analyses of liver leukocytes from infected\n                      <jats:italic toggle=\"yes\">\n                        Ifnar1\n                        <jats:sup>\u0394Hep<\/jats:sup>\n                      <\/jats:italic>\n                      mice revealed a rapid accumulation of activated NK cells in the liver within 2 days. HAV infection and liver inflammation were brief and substantially reduced in magnitude in these mice compared to global\n                      <jats:italic toggle=\"yes\">\n                        Ifnar1\n                        <jats:sup>-\/-<\/jats:sup>\n                      <\/jats:italic>\n                      knockout mice that failed to induce substantial antiviral NK cell responses. NK cells were the principal source of interferon (IFN)-\u03b3 in\n                      <jats:italic toggle=\"yes\">\n                        Ifnar1\n                        <jats:sup>\u0394Hep<\/jats:sup>\n                      <\/jats:italic>\n                      mice.\n                      <jats:italic toggle=\"yes\">\n                        Ifnar1\n                        <jats:sup>\u0394Hep<\/jats:sup>\n                      <\/jats:italic>\n                      mice that were experimentally depleted of NK cells or IFN-\u03b3 showed greatly increased viral replication and liver damage. Moreover, IFN-\u03b3 alone was sufficient to suppress HAV replication in primary mouse hepatocytes. Collectively, these findings establish a critical role for type-I IFN induction of NK cells, their expression of IFN-\u03b3, and protection against hepatitis A.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Hepatitis A virus remains a leading cause of foodborne illness among unvaccinated individuals. Infection can result in severe liver injury that can progress to fatal fulminant viral hepatitis. Despite its clinical significance, the molecular, genetic, and cellular factors influencing infection severity remain poorly understood. Previous studies of patient blood have suggested that natural killer (NK) cells cause liver injury during infection. In this study, we used mouse models of infection to characterize early cellular defenses to infection and identified a critical role for NK cells and interferon-\u03b3 in conferring rapid immune protection rather than pathogenesis.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01395-25","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T13:00:20Z","timestamp":1758286820000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Natural killer cells and IFN-\u03b3 protect against liver injury during HAV infection in mice"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3892-7605","authenticated-orcid":false,"given":"Ichiro","family":"Misumi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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