The Autoimmunity-Associated Minor Allele of PTPN22 Enhances Antiviral Immunity During Coronavirus Infection

Abstract

Abstract The deadly consequences of viral infection were clearly demonstrated by the COVID-19 pandemic. Therefore, identifying new therapeutic targets to enhance our antiviral immunity and combat virus infection is essential, such as the immune-regulatory gene PTPN22. 5-15% of North Americans express a PTPN22 alternative allele which is linked with multiple autoimmune diseases. However, there is a significant research gap regarding the role of PTPN22 and its common allele during viral infection. To address this, we used CRISPR/Cas9 generated Ptpn22 knockout (PEP-null) and Ptpn22 minor allele expressing (PEP-619WW) mice and infected them with the common murine model of coronavirus, Mouse Hepatitis Virus (MHV) A59. We hypothesize that PEP-null and PEP-619WW mice have enhanced antiviral immunity during coronavirus infection. Following MHV A59 infection, PEP-null and PEP-619WW mice have reduced weight loss and increased survival over WT mice. Additionally, PEP-null and PEP-619WW mice have enhanced innate immunity, such as increased Natural Killer (NK) cell numbers. Furthermore, we show that PEP-null and PEP-619WW innate immune cells offer enhanced protection during MHV A59 infection, but lymphocytes are necessary for survival. These results demonstrate that PEP-null and PEP-619WW are beneficial during coronavirus infection. This research sets the precedent to interrogate the role of Ptpn22 in other RNA virus infections and as a novel therapeutic target to enhance antiviral immunity.