 This study uses a genome-wide CRISPR dropout screen and multi-omics data analysis to identify previously unknown antiviral host factors that modulate viral entry and replication, including components of VAT-Parses, ESCRT, end-like acylation pathways, the cohesin complex, and KLF5. The study also confirms the antiviral effects of three identified candidates, DESAP2, VTA1, KLF5, and highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19.