Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection

  1. Jin Wei
  2. Mia Madel Alfajaro
  3. Ruth E. Hanna
  4. Peter C. DeWeirdt
  5. Madison S. Strine
  6. William J. Lu-Culligan
  7. Shang-Min Zhang
  8. Vincent R. Graziano
  9. Cameron O. Schmitz
  10. Jennifer S. Chen
  11. Madeleine C. Mankowski
  12. Renata B. Filler
  13. Victor Gasque
  14. Fernando de Miguel
  15. Huacui Chen
  16. Kasopefoluwa Oguntuyo
  17. Laura Abriola
  18. Yulia V. Surovtseva
  19. Robert C. Orchard
  20. Benhur Lee
  21. Brett Lindenbach
  22. Katerina Politi
  23. David van Dijk
  24. Matthew D. Simon
  25. Qin Yan
  26. John G. Doench
  27. Craig B. Wilen
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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 a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-β signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.

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