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; Weiyi Peng

doi:10.1038/s41467-023-44175-1

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

Nat Commun. 2024 Jan 2;15(1):109. doi: 10.1038/s41467-023-44175-1.

Authors

Jiakai Hou^#¹, Yanjun Wei^#², Jing Zou^#³, Roshni Jaffery¹, Long Sun³, Shaoheng Liang^{2

4

5}, Ningbo Zheng¹, Ashley M Guerrero¹, Nicholas A Egan¹, Ritu Bohat¹, Si Chen¹, Caishang Zheng², Xiaobo Mao⁶, S Stephen Yi^{7

8}, Ken Chen², Daniel J McGrail⁹, Nidhi Sahni^{2

10}, Pei-Yong Shi^{11

12

13

14

15

16}, Yiwen Chen^{17

18}, Xuping Xie^{19

20}, Weiyi Peng²¹

Affiliations

¹ Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
² Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
⁴ Department of Computer Science, Rice University, Houston, TX, USA.
⁵ Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Oncology, Livestrong Cancer Institutes, and Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
⁸ Interdisciplinary Life Sciences Graduate Programs (ILSGP) and Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, USA.
⁹ Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
¹⁰ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹² Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹³ Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁴ Sealy Center for Structural Biology & Molecular Biophysics, The University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁵ Institute for Translational Science, The University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁶ Sealy Institute for Drug Discovery, The University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁷ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ychen26@mdanderson.org.
¹⁸ Quantitative Sciences Program, MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, TX, USA. ychen26@mdanderson.org.
¹⁹ Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA. xuxie@UTMB.edu.
²⁰ Sealy Institute for Drug Discovery, The University of Texas Medical Branch, Galveston, TX, USA. xuxie@UTMB.edu.
²¹ Department of Biology and Biochemistry, University of Houston, Houston, TX, USA. wpeng2@Central.uh.edu.

^# Contributed equally.

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.

MeSH terms

Antiviral Agents / pharmacology
COVID-19*
Genome-Wide Association Study
Humans
Multiomics
SARS-CoV-2

Substances

Antiviral Agents

Abstract

MeSH terms

Substances

Grants and funding