Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection

Wei, Jin; Alfajaro, Mia Madel; Hanna, Ruth E.; DeWeirdt, Peter C.; Strine, Madison S.; Lu-Culligan, William J.; Zhang, Shang-Min; Graziano, Vincent R.; Schmitz, Cameron O.; Chen, Jennifer S.; Mankowski, Madeleine C.; Filler, Renata B.; Gasque, Victor; de Miguel, Fernando; Chen, Huacui; Oguntuyo, Kasopefoluwa; Abriola, Laura; Surovtseva, Yulia V.; Orchard, Robert C.; Lee, Benhur; Lindenbach, Brett; Politi, Katerina; van Dijk, David; Simon, Matthew D.; Yan, Qin; Doench, John G.; Wilen, Craig B.

Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.