An Autoimmunity-associated allele of PTPN22 enhances innate antiviral immunity to protect against acute coronavirus infection

Abstract Allelic variation can impact viral clearance and disease severity. Still, our understanding of the effect of the autoimmunity-associated allelic variant of Ptpn22 (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 Ptpn22 (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 IFNγ and enhanced IFNγ 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 Ptpn22 within NK cells and demonstrates that the Ptpn22 allelic variant augments NK cell function and is beneficial during coronavirus infection. Significance Statement Approximately 5-15% of the North American population has the PTPN22 1858C>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 PTPN22 1858C>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 PTPN22 1858C>T allele impacts the immune response during acute, moribund infections. Using mice that are homozygous for the equivalent, autoimmunity-associated allele in Ptpn22 , we demonstrate that this allele uniquely augments innate immunity and enhances Natural Killer cell function to protect against coronavirus infection.