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      Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection

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      Cell

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          Abstract

          Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here, we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, MERS-CoV, bat coronavirus HKU5 expressing the SARS-CoV-1 spike, and VSV expressing the SARS-CoV-2 spike. We identify 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 HMGB1 regulates ACE2 expression and is critical for viral 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. Together this identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS-lineage specific and pan-coronavirus host factors that regulate susceptibility to highly pathogenic coronaviruses.

          Highlights

          • 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.

          Abstract

          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 or pseudoviruses presenting SARS-CoV-1 or -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 plays a critical role in ACE2 expression.

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          Author and article information

          Journal
          Cell
          Cell
          Cell
          Elsevier Inc.
          0092-8674
          1097-4172
          20 October 2020
          20 October 2020
          Affiliations
          [1 ]Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06520, USA
          [2 ]Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA
          [3 ]Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
          [4 ]Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520, USA
          [5 ]Department of Cell Biology, Yale University, New Haven, CT 06520, USA
          [6 ]Chemical Biology Institute, Yale University, West Haven, CT 06516, USA
          [7 ]Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
          [8 ]Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA
          [9 ]Department of Computer Science, Yale University, New Haven, CT 06520, USA
          [10 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
          [11 ]Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516, USA
          [12 ]Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
          [13 ]Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06520, USA
          [14 ]Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA
          [15 ]Department of Pediatric Oncology, Dana–Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
          [16 ]Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
          [17 ]Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA
          Author notes
          []Corresponding author ,
          [18]

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          Article
          S0092-8674(20)31392-1
          10.1016/j.cell.2020.10.028
          7574718
          © 2020 Elsevier Inc.

          Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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          Cell biology

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