Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection

Wei, Jin; Alfajaro, Mia Madel; DeWeirdt, Peter C.; Hanna, Ruth E.; Lu-Culligan, William J.; Cai, Wesley L.; Strine, Madison S.; Zhang, Shang-Min; Graziano, Vincent R.; Schmitz, Cameron O.; Chen, Jennifer S.; Mankowski, Madeleine C.; Filler, Renata B.; Ravindra, Neal G.; Gasque, Victor; de Miguel, Fernando J.; Patil, Ajinkya; Chen, Huacui; Oguntuyo, Kasopefoluwa Y.; Abriola, Laura; Surovtseva, Yulia V.; Orchard, Robert C.; Lee, Benhur; Lindenbach, Brett D.; Politi, Katerina; van Dijk, David; Kadoch, Cigall; 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 genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, MERS-CoV, bat coronavirus HKU5 expressing the SARS-CoV-1 spike, and VSV expressing the SARS-CoV-2 spike. We identify known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways including HMGB1 and the SWI/SNF chromatin remodeling complex that are SARS-lineage and pan-coronavirus specific, respectively. We show HMGB1 regulates ACE2 expression and is critical for viral entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. Together this identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS-lineage specific and pan-coronavirus host factors that regulate susceptibility to highly pathogenic coronaviruses.