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Still, our understanding of the effect of the autoimmunity-associated allelic variant of\n                  <jats:italic>Ptpn22<\/jats:italic>\n                  (PEP-R619W) on antiviral immunity remains incomplete, as previous reports have only focused on chronic Lymphocytic Choriomeningitis virus (LCMV) infection. This research defines how the loss of\n                  <jats:italic>Ptpn22<\/jats:italic>\n                  (PEP-null) and PEP-R619W changes antiviral immunity during an acute coronavirus infection. We address the hypothesis that CRISPR\/Cas9-generated PEP-null and PEP-R619W mice have enhanced antiviral immunity over PEP-WT mice during coronavirus infection. Following Mouse Hepatitis Virus (MHV) A59 infection, we interrogated pathology, cytokine production, and cellular responses in the blood, spleen, and liver of PEP-WT, PEP-null, and PEP-R619W mice. Key findings show that PEP-R619W mice have reduced viral titer and weight loss, increased survival, and more mature natural killer (NK) cells in the liver and spleen compared to PEP-WT mice. Interestingly, protection against disease in PEP-null mice was inoculation-dose-dependent, whereas PEP-R619W conferred immunity regardless of infection dose. Further, Rag1-\/- PEP-R619W mice had increased survival and reduced viral titer over Rag1-\/- PEP-WT mice. PEP-R619W mice also had higher concentrations of IFN\u03b3 and enhanced IFN\u03b3 production by mature NK cells in the liver at 3 days post-infection. Finally, NK cell depletion elevated PEP-R619W viral titer to similar levels as PEP-WT mice. This is one of the first studies investigating the role of\n                  <jats:italic>Ptpn22<\/jats:italic>\n                  within NK cells and demonstrates that the\n                  <jats:italic>Ptpn22<\/jats:italic>\n                  allelic variant augments NK cell function and is beneficial during coronavirus infection.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Approximately 5-15% of the North American population has the\n                    <jats:italic>PTPN22<\/jats:italic>\n                    1858C&gt;T allele, which has been linked with numerous autoimmune diseases and is considered the highest non-HLA risk allele for autoimmunity. Due to this link, the\n                    <jats:italic>PTPN22<\/jats:italic>\n                    1858C&gt;T allele is often considered pathologic or detrimental. However, recent studies have demonstrated the benefit of this allele in protection from chronic virus infection and some cancers. Yet, a significant research gap remains in understanding how the\n                    <jats:italic>PTPN22<\/jats:italic>\n                    1858C&gt;T allele impacts the immune response during acute, moribund infections. Using mice that are homozygous for the equivalent, autoimmunity-associated allele in\n                    <jats:italic>Ptpn22<\/jats:italic>\n                    , we demonstrate that this allele uniquely augments innate immunity and enhances Natural Killer cell function to protect against coronavirus infection.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.15.664967","type":"posted-content","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T05:50:14Z","timestamp":1752904214000},"source":"Crossref","is-referenced-by-count":0,"title":["An Autoimmunity-associated allele of\n                  <i>PTPN22<\/i>\n                  enhances innate antiviral immunity to protect against acute coronavirus infection"],"prefix":"10.64898","author":[{"given":"Alec M.","family":"Bevis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn 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