2. Academic Validation
  3. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

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

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: jdoench@broadinstitute.org.
  • 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: craig.wilen@yale.edu.
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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