期刊
NATURE GENETICS
卷 54, 期 8, 页码 1078-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-022-01131-x
关键词
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资金
- National Science Foundation (NSF) Graduate Research Fellowship [DGE-1752814]
- NIH/National Cancer Institute (NCI) F32 Postdoctoral Fellowship [1F32CA250324-01]
- American Cancer Society Postdoctoral Fellowship [PF-20143-01-LIB]
- NSF Graduate Research Fellowship
- Caring Together Research Fund
- Department of Defense pilot grant [W81XWH-21-1-0256]
- NCI [R01CA200423]
- North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill
- North Carolina Coronavirus Relief Fund
- National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute institutes of the NIH [UH3-HL123645, P01-HL110873, R01-HL136961, P30-DK065988-13, P01-HL108808]
- Cystic Fibrosis Foundation [OKUDA20G0, R01-AI157253]
- NIH [DP5OD021369, K08AI128043]
- NCI Center Core Support Grant [5P30CA016086-41]
- Burroughs Wellcome Fund (Investigators in the Pathogenesis of Infectious Disease)
- Applied Genomics in Infectious Diseases, NIH [5T32 AI007502]
- NIH/NIAID [AI109022, R21 AI156731]
- Burroughs Wellcome Fund
- Ludwig Family Foundation
- Mathers Foundation
- Fast Grants
This study identified mucins as key host factors restricting viral infection, through genome-wide CRISPR knockout and activation screens in human lung epithelial cells expressing the SARS-CoV-2 entry factors ACE2 and TMPRSS2. These mucins serve as a significant viral restriction network inhibiting SARS-CoV-2 infection and other respiratory viruses. The findings provide a starting point for new host-directed therapeutics and highlight airway mucins as an important host defense mechanism.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism. Genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2 identify mucins as key host factors restricting viral infection.
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