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 Xie () and Weiyi Peng ()
Additional contact information
Jiakai Hou: University of Houston
Yanjun Wei: The University of Texas MD Anderson Cancer Center
Jing Zou: The University of Texas Medical Branch
Roshni Jaffery: University of Houston
Long Sun: The University of Texas Medical Branch
Shaoheng Liang: The University of Texas MD Anderson Cancer Center
Ningbo Zheng: University of Houston
Ashley M. Guerrero: University of Houston
Nicholas A. Egan: University of Houston
Ritu Bohat: University of Houston
Si Chen: University of Houston
Caishang Zheng: The University of Texas MD Anderson Cancer Center
Xiaobo Mao: Johns Hopkins University School of Medicine
S. Stephen Yi: The University of Texas at Austin
Ken Chen: The University of Texas MD Anderson Cancer Center
Daniel J. McGrail: Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic
Nidhi Sahni: The University of Texas MD Anderson Cancer Center
Pei-Yong Shi: The University of Texas Medical Branch
Yiwen Chen: The University of Texas MD Anderson Cancer Center
Xuping Xie: The University of Texas Medical Branch
Weiyi Peng: University of Houston

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44175-1

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