ABSTRACT
Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we performed a genome-wide CRISPR dropout screen and integrated analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-seq, and host-virus proteins or protein/RNA interactome. This study has uncovered many host factors that were missed by previous studies, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulated viral entry and/or replication. The cohesin complex was also identified as a novel anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discovered an anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which was up-regulated and harbored genetic variations linked to the COVID-19 patients with severe symptoms. Our results provide a resource for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.