1. Functional landscape of SARS-CoV-2 cellular restriction
- Author
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Trey Ideker, Megan L. Shaw, Sara Brin Rosenthal, Matthew Urbanowski, Sumit K. Chanda, Chunxiang Wu, Thomas J. Hope, Yong Xiong, Charlotte A. Stoneham, Matthew B. Frieman, Aaron L. Oom, John C. Guatelli, Dexter Pratt, Sophie Liu, Christopher Churas, Courtney Nguyen, Anshu P. Gounder, Mary K. Lewinski, Lisa Miorin, Adolfo García-Sastre, Mark E. Becker, Stuart Weston, Yuan Pu, Alan M. O’Neill, Max W. Chang, Laura Martin-Sancho, Christopher Benner, Fan Zheng, Heather M. Curry, Paul D. De Jesus, Judd F. Hultquist, Ariel Rodriguez-Frandsen, Xin Yin, and Lars Pache
- Subjects
Protein Conformation ,viruses ,Golgi Apparatus ,RNA-binding protein ,Endoplasmic Reticulum ,Virus Replication ,Medical and Health Sciences ,0302 clinical medicine ,Interferon ,Chlorocebus aethiops ,Innate ,Orf7a ,2.1 Biological and endogenous factors ,Aetiology ,innate immunity ,Lung ,Virus Release ,0303 health sciences ,Tumor ,Effector ,viral evasion ,virus diseases ,interferon ,Biological Sciences ,CD ,Molecular Docking Simulation ,Infectious Diseases ,Interferon Type I ,Interferon Regulatory Factors ,Host-Pathogen Interactions ,Pneumonia & Influenza ,Infection ,Signal Transduction ,Protein Binding ,medicine.drug ,Resource ,BST2 ,Biology ,GPI-Linked Proteins ,Cell Line ,ISG ,Vaccine Related ,Viral Proteins ,03 medical and health sciences ,Viral entry ,Biodefense ,Genetics ,medicine ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Antigens ,Vero Cells ,Molecular Biology ,Gene ,030304 developmental biology ,Binding Sites ,Innate immune system ,SARS-CoV-2 ,Prevention ,alpha-Helical ,Immunity ,Pneumonia ,Cell Biology ,Virus Internalization ,Virology ,HEK293 Cells ,Emerging Infectious Diseases ,Good Health and Well Being ,Gene Expression Regulation ,Viral replication ,Tetherin ,beta-Strand ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
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/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19., Graphical abstract, Deficient interferon responses to SARS-CoV-2 infection have been associated with severe COVID-19. Martin-Sancho et al. utilized a gain-of-function screen to identify interferon-stimulated effectors that govern innate immune responses to SARS-CoV-2. These factors could underlie genetic predisposition to severe COVID-19 and can serve as candidates for development of antiviral therapies.
- Published
- 2021