Cell
Volume 184, Issue 1, 7 January 2021, Pages 76-91.e13
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Article
Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

https://doi.org/10.1016/j.cell.2020.10.028Get rights and content
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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

Summary

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

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

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