TY - JOUR
T1 - Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection
AU - Hou, Jiakai
AU - Wei, Yanjun
AU - Zou, Jing
AU - Jaffery, Roshni
AU - Sun, Long
AU - Liang, Shaoheng
AU - Zheng, Ningbo
AU - Guerrero, Ashley M.
AU - Egan, Nicholas A.
AU - Bohat, Ritu
AU - Chen, Si
AU - Zheng, Caishang
AU - Mao, Xiaobo
AU - Yi, S. Stephen
AU - Chen, Ken
AU - McGrail, Daniel J.
AU - Sahni, Nidhi
AU - Shi, Pei Yong
AU - Chen, Yiwen
AU - Xie, Xuping
AU - Peng, Weiyi
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/1/2
Y1 - 2024/1/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85181229631
UR - https://www.scopus.com/pages/publications/85181229631#tab=citedBy
U2 - 10.1038/s41467-023-44175-1
DO - 10.1038/s41467-023-44175-1
M3 - Article
C2 - 38168026
AN - SCOPUS:85181229631
SN - 2041-1723
VL - 15
SP - 109
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 109
ER -