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

Spalinger, M. R.; Hai, R.; Li, J.; Santos, A. N.; Nordgren, T. M.; Tremblay, M. L.; Eckmann, L.; Hanson, E.; Scharl, M.; Wu, X.; Boland, B. S.; McCole, D. F.

doi:10.1101/2020.12.09.416586

bioRxiv · 10.1101/2020.12.09.416586

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

Spalinger, M. R.·Hai, R.·Li, J.·Santos, A. N.·Nordgren, T. M.·Tremblay, M. L.·Eckmann, L.·Hanson, E.·Scharl, M.·Wu, X.·Boland, B. S.·McCole, D. F.

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Abstract

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. While fatality rates are higher among the elderly and those with underlying comorbidities2, 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.3-7 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.

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Spalinger, M. R., Hai, R., Li, J., Santos, A. N., Nordgren, T. M., Tremblay, M. L., Eckmann, L., Hanson, E., Scharl, M., Wu, X., Boland, B. S., McCole, D. F.. 2020-12-09. 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. https://doi.org/10.1101/2020.12.09.416586

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