Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Coronavirus disease (COVID-19), caused by SARS-CoV-2, has affected over 65 million individuals and killed over 1.5 million persons (December 8, 2020; [www.who.int][1])[1][2]. While fatality rates are higher among the elderly and those with underlying comorbidities[2][3], host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases.[3][4]–[7][5] We report that the autoimmune PTPN2 risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry mediated by SARS-CoV-2 spike protein. Elevated ACE2 expression and viral entry were mediated by increased JAK-STAT signalling, and were reversed by the JAK inhibitor, tofacitinib. Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk. ### Competing Interest Statement BSB consulted for Pfizer Inc, unrelated to the content of this article. DFM has received investigator-initiated research awards from the makers of tofacitinib (Pfizer Inc.) through the ASPIRE-Pfizer JAK-STAT in IBD Research Program for studies unrelated to the content of this manuscript. [1]: https://www.who.int [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-7