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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, 01/2021, Volume: 184, Issue: 1Journal Article
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. Display omitted •Developed monkey CRISPR library to screen pathogenic coronaviruses in Vero-E6 cells•Screens identified genes that are SARS-CoV-2, MERS-CoV, and pan-coronavirus specific•Therapeutic targets, including SMARCA4, identified for SARS-CoV-2 infection•HMGB1 is novel regulator of ACE2 expression and critical for viral entry To identify potential therapeutic targets for SARS-CoV-2 and related pathogenic coronaviruses, Wei et al. conduct genome-wide CRISPR screens in Vero-E6 cells using SARS-CoV-2, MERS-CoV, and pseudoviruses presenting SARS-CoV-1 or SARS-CoV-2 spike proteins. They identify pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively, and demonstrate that HMGB1 is critical for SARS lineage viral entry because it has a critical role in ACE2 expression.
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