Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

Cell. 2021 Jan 7;184(1):76-91.e13. doi: 10.1016/j.cell.2020.10.028.

Jin Wei ¹, Mia Madel Alfajaro ¹, Peter C DeWeirdt ², Ruth E Hanna ², William J Lu-Culligan ³, Wesley L Cai ⁴, Madison S Strine ¹, Shang-Min Zhang ⁴, Vincent R Graziano ¹, Cameron O Schmitz ¹, Jennifer S Chen ¹, Madeleine C Mankowski ¹, Renata B Filler ¹, Neal G Ravindra ⁵, Victor Gasque ⁵, Fernando J de Miguel ⁶, Ajinkya Patil ⁷, Huacui Chen ⁴, Kasopefoluwa Y Oguntuyo ⁸, Laura Abriola ⁹, Yulia V Surovtseva ⁹, Robert C Orchard ¹⁰, Benhur Lee ⁸, Brett D Lindenbach ¹¹, Katerina Politi ¹², David van Dijk ⁵, Cigall Kadoch ⁷, Matthew D Simon ¹³, Qin Yan ⁶, John G Doench ¹⁴, Craig B Wilen ¹⁵

Affiliations

1 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.
2 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3 Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520, USA; Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Chemical Biology Institute, Yale University, West Haven, CT 06516, USA.
4 Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
5 Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA.
6 Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA.
7 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9 Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516, USA.
10 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
11 Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06520, USA.
12 Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA; Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
13 Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520, USA; Chemical Biology Institute, Yale University, West Haven, CT 06516, USA.
14 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].
15 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; Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].

PMID: 33147444 DOI: 10.1016/j.cell.2020.10.028

Abstract

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.

Keywords

COVID-19; CRISPR screen; Epigenetics; HMGB1; MERS-CoV; Middle East Respiratory Syndrome; SARS-CoV-2; SWI/SNF complex; Severe Acute Respiratory Syndrome.

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