Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection

Jiakai Hou, Yanjun Wei, Jing Zou, Roshni Jaffery, Long Sun, Shaoheng Liang, Ningbo Zheng, Ashley M. Guerrero, Nicholas A. Egan, Ritu Bohat, Si Chen, Caishang Zheng, Xiaobo Mao, S. Stephen Yi, Ken Chen, Daniel J. McGrail, Nidhi Sahni, Pei-Yong Shi, Yiwen Chen, Xuping XieWeiyi Peng

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 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 currently underappreciated, 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 harbors 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 further resources for understanding the host anti-viral network during SARS-CoV-2 infection and may help develop new countermeasure strategies.

Original languageEnglish (US)
Article number109
JournalNature communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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