Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection [ATAC-seq]

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, identifying 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, the alarmin HMGB1, and the transcription factors Smad3 and Smad4. Small molecule inhibitors of these pathways inhibited SARS-CoV-2-infection in both monkey and human cells, demonstrating the conserved role of these genetic hits across species. We also revealed that HMGB1 is a novel regulator of ACE2 expression and 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. Overall design: RNAseq, ChIPseq (H3K4me3, H3K27ac) and ATACseq of Vero-E6 cell lines in control sgRNA and HMGB1 KO sgRNA conditions.