Functional Landscape of SARS-CoV-2 Cellular Restriction, Martin-Sancho et al.
A deficient interferon response to SARS-CoV-2 infection has been implicated as a determinant of severe COVID-19. To identify the molecular effectors that govern interferon control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human interferon stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of ER-Golgi-resident ISGs inhibiting viral assembly-egress. These included broad-acting antiviral ISGs, and eight ISGs that specifically inhibited SARS-CoV-2 and -1 replication. Amongst the broad-acting ISGs was BST2/tetherin, which impeded viral release, and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.