Journal
MOLECULAR CELL
Volume 81, Issue 12, Pages 2656-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.04.008
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Funding
- SBP Medical Discovery Institute
- Icahn School of Medicine at Mount Sinai: DOD [W81XWH2010270, DHIPC U19 AI118610, Fluomics/NOSI U19 AI135972]
- Open Philanthropy Project [2020-215611 (5384)]
- DARPA [HR0011-19-2-0020]
- CRIP (Center for Research on Influenza Pathogenesis)
- NIAID [HHSN272201400008C]
- Northwestern University Feinberg School of Medicine: a CTSA supplement [UL1 TR002389]
- CTSA supplement
- Dixon family [UL1 TR001422]
- Cancer Center supplement [P30 CA060553]
- NIH at UC San Diego [R37AI081668]
- James B. Pendleton Charitable Trust
- U.S. Department of Defense (DOD) [W81XWH2010270] Funding Source: U.S. Department of Defense (DOD)
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This study identified specific ISGs that control viral replication and assembly/release of SARS-CoV-2, including BST2/tetherin, offering insights into host determinants impacting disease severity and potential therapeutic strategies for COVID-19.
A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of -function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARSCoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.
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