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Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection. 2021
Jin Wei, and
Mia Madel Alfajaro, and
Peter C DeWeirdt, and
Ruth E Hanna, and
William J Lu-Culligan, and
Wesley L Cai, and
Madison S Strine, and
Shang-Min Zhang, and
Vincent R Graziano, and
Cameron O Schmitz, and
Jennifer S Chen, and
Madeleine C Mankowski, and
Renata B Filler, and
Neal G Ravindra, and
Victor Gasque, and
Fernando J de Miguel, and
Ajinkya Patil, and
Huacui Chen, and
Kasopefoluwa Y Oguntuyo, and
Laura Abriola, and
Yulia V Surovtseva, and
Robert C Orchard, and
Benhur Lee, and
Brett D Lindenbach, and
Katerina Politi, and
David van Dijk, and
Cigall Kadoch, and
Matthew D Simon, and
Qin Yan, and
John G Doench, and
Craig B Wilen
Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
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.
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