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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.
Cell; 2020 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-33147444
Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified 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 that HMGB1 regulates ACE2 expression and is critical for 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. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.