ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/025/SRR26552525/SRR26552525_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/031/SRR26552531/SRR26552531_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/034/SRR26552534/SRR26552534_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/029/SRR26552529/SRR26552529_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/028/SRR26552528/SRR26552528_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/023/SRR26552523/SRR26552523_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/023/SRR26552523/SRR26552523_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/029/SRR26552529/SRR26552529_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/027/SRR26552527/SRR26552527_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/026/SRR26552526/SRR26552526_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/032/SRR26552532/SRR26552532_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/033/SRR26552533/SRR26552533_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/030/SRR26552530/SRR26552530_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/024/SRR26552524/SRR26552524_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/032/SRR26552532/SRR26552532_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/034/SRR26552534/SRR26552534_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/033/SRR26552533/SRR26552533_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/025/SRR26552525/SRR26552525_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/026/SRR26552526/SRR26552526_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/030/SRR26552530/SRR26552530_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/024/SRR26552524/SRR26552524_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/031/SRR26552531/SRR26552531_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/027/SRR26552527/SRR26552527_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR265/028/SRR26552528/SRR26552528_2.fastq.gzprimary200OKGenomicsCenter for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinichttps://www.ebi.ac.uk/ena/browser/view/PRJNA1032949Homo sapiensxref:PubMed:38168026Host 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 perform a genome-wide CRISPR dropout screen and integrate 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 uncovers many host factors that are missed by previous studies, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of three-dimensional chromatin organization in mediating host-viral interaction. Furthermore, we discover another anti-viral regulator KLF5, a transcriptional factor involved in sphingolipid metabolism, which is up-regulated and harbored genetic variations linked to COVID-19 patients with severe symptoms. Anti-viral effects of three identified candidates (DAZAP2/VTA1/KLF5) are confirmed individually. Molecular characterization of DAZAP2/VTA1/KLF5-knockout cells highlights the involvement of genes related to the coagulation system in determining the severity of COVID-19. Together, our results provide wealthy resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies. Overall design: A549 derived KO cell lines and related negative control cell line were preseeded and cultured for 24 hrs prior to RNA isolation and stranded RNAseq.ENAfalseComparing the transcriptomic profiles of anti-viral candidates knockout cellsComparing the transcriptomic profiles of anti-viral candidates knockout cells2025-09-242023-11-01PRJNA1032949GSE246452960638168026