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

Jin Wei1,2, Mia Madel Alfajaro1,2, Ruth E. Hanna3, Peter C. DeWeirdt3, Madison S. Strine1,2, William J. Lu-Culligan4,, Shang-Min Zhang5, David van Dijk6, Matthew D. Simon4, Qin Yan5,, John G. Doench3, Craig B. Wilen1,2

1Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA, 2Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA, 3Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA, 4Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA, 5Department of Pathology, Yale School of Medicine, New Haven, CT, USA, 6Department of Medicine, Yale School of Medicine, New Haven, CT, USA 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 in Vero E6 cells and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L.

We 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.