The autoimmunity-associated minor allele of PTPN22 enhances innate antiviral immunity during coronavirus infection 3695

Abstract Description Allelic variation can impact viral clearance and disease severity. Mice expressing the autoimmunity-associated allelic variant of Ptpn22 (PEP-R619W) clear chronic LCMV-cl13 infection whereas PEP-WT mice do not. However, little is known about Ptpn22 during other virus infections. This research defines how the loss of Ptpn22 (PEP-null) and PEP-R619W changes antiviral immunity during coronavirus infection. We addressed 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 spleen, blood, and liver of PEP-WT, PEP-null, and PEP-R619W mice. Key findings show that PEP-R619W mice have 1) reduced viral titer and weight loss, 2) increased survival, and 3) more mature NK cells in the liver and spleen over PEP-WT and PEP-null mice. 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 of PEP-WT mice. This is one of the first studies investigating the role of Ptpn22 within NK cells. We demonstrate that the Ptpn22 allelic variant augments NK cell function and is beneficial during coronavirus infection. Funding Sources NIH Chemical Biology T32 Training Grant GM13206 Topic Categories Viral Immunology (VIR)