D Xu, W Jiang, . Wu, RG Gaudet, E-S Park, M Su, SK Cheppali, NR Cheemarla, P Kumar, PD Uchil, JR Grover, EF Foxman, CM Brown, PJ Stansfeld, J Bewersdorf, W Mothes, E Karatekin, CB Wilen, and JD MacMicking

Understanding protective immunity to COVID-19 facilitates preparedness for future pandemics and combats new SARS-CoV-2 variants emerging in the human population. Neutralizing antibodies have been widely studied; however, on the basis of large-scale exome sequencing of protected versus severely ill patients with COVID-19, local cell-autonomous defence is also crucial. Here we identify phospholipid scramblase 1 (PLSCR1) as a potent cell-autonomous restriction factor against live SARS-CoV-2 infection in parallel genome-wide CRISPR–Cas9 screens of human lung epithelia and hepatocytes before and after stimulation with interferon-γ (IFNγ). IFNγ-induced PLSCR1 not only restricted SARS-CoV-2 USA-WA1/2020, but was also effective against the Delta B.1.617.2 and Omicron BA.1 lineages. . Our mechanistic studies, together with reports that COVID-associated PLSCR1 mutations are found in some susceptible people, identify an anti-coronavirus protein that interferes at a late entry step before viral RNA is released into the host-cell cytosol.

Nature. July 2023