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

被引:0
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作者
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
Weiyi Peng
机构
[1] University of Houston,Department of Biology and Biochemistry
[2] The University of Texas MD Anderson Cancer Center,Department of Bioinformatics and Computational Biology
[3] The University of Texas Medical Branch,Department of Biochemistry & Molecular Biology
[4] Rice University,Department of Computer Science
[5] Johns Hopkins University School of Medicine,Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology
[6] The University of Texas at Austin,Department of Oncology, Livestrong Cancer Institutes, and Department of Biomedical Engineering
[7] The University of Texas at Austin,Interdisciplinary Life Sciences Graduate Programs (ILSGP) and Oden Institute for Computational Engineering and Sciences (ICES)
[8] Center for Immunotherapy and Precision Immuno-Oncology,Department of Epigenetics and Molecular Carcinogenesis
[9] Cleveland Clinic,Institute for Human Infections and Immunity
[10] The University of Texas MD Anderson Cancer Center,Sealy Institute for Vaccine Sciences
[11] The University of Texas Medical Branch,Sealy Center for Structural Biology & Molecular Biophysics
[12] The University of Texas Medical Branch,Institute for Translational Science
[13] The University of Texas Medical Branch,Sealy Institute for Drug Discovery
[14] The University of Texas Medical Branch,Computational Biology Department, School of Computer Science
[15] The University of Texas Medical Branch,undefined
[16] Quantitative Sciences Program,undefined
[17] MD Anderson Cancer Center,undefined
[18] UT Health Graduate School of Biomedical Sciences,undefined
[19] Carnegie Mellon University,undefined
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摘要
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.
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