Functional landscape of SARS-CoV-2 cellular restriction

Laura Martin-Sancho; Mary K Lewinski; Lars Pache; Charlotte A Stoneham; Xin Yin; Mark E Becker; Dexter Pratt; Christopher Churas; Sara B Rosenthal; Sophie Liu; Stuart Weston; Paul D De Jesus; Alan M O'Neill; Anshu P Gounder; Courtney Nguyen; Yuan Pu; Heather M Curry; Aaron L Oom; Lisa Miorin; Ariel Rodriguez-Frandsen; Fan Zheng; Chunxiang Wu; Yong Xiong; Matthew Urbanowski; Megan L Shaw; Max W Chang; Christopher Benner; Thomas J Hope; Matthew B Frieman; Adolfo García-Sastre; Trey Ideker; Judd F Hultquist; John Guatelli; Sumit K Chanda

doi:10.1016/j.molcel.2021.04.008

Functional landscape of SARS-CoV-2 cellular restriction

Mol Cell. 2021 Jun 17;81(12):2656-2668.e8. doi: 10.1016/j.molcel.2021.04.008. Epub 2021 Apr 13.

Authors

Laura Martin-Sancho¹, Mary K Lewinski², Lars Pache¹, Charlotte A Stoneham², Xin Yin¹, Mark E Becker³, Dexter Pratt⁴, Christopher Churas⁴, Sara B Rosenthal⁴, Sophie Liu⁴, Stuart Weston⁵, Paul D De Jesus¹, Alan M O'Neill⁶, Anshu P Gounder¹, Courtney Nguyen¹, Yuan Pu¹, Heather M Curry¹, Aaron L Oom², Lisa Miorin⁷, Ariel Rodriguez-Frandsen¹, Fan Zheng⁴, Chunxiang Wu⁸, Yong Xiong⁸, Matthew Urbanowski⁹, Megan L Shaw¹⁰, Max W Chang⁴, Christopher Benner⁴, Thomas J Hope³, Matthew B Frieman⁵, Adolfo García-Sastre¹¹, Trey Ideker¹², Judd F Hultquist¹³, John Guatelli², Sumit K Chanda¹⁴

Affiliations

¹ Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
² Department of Medicine, University of California San Diego, and the VA San Diego Healthcare System, San Diego, CA 92161, USA.
³ Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁴ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁵ Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁶ Department of Dermatology, University of California San Diego, La Jolla, CA 92093, USA.
⁷ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.
⁸ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA.
⁹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.
¹⁰ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; Department of Medical Biosciences, University of the Western Cape, Cape Town 7535, South Africa.
¹¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; The Tisch Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.
¹² Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093, USA.
¹³ Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹⁴ Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: schanda@sbpdiscovery.org.

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.

Keywords: BST2; ISG; Orf7a; SARS-CoV-2; innate immunity; interferon; viral evasion.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, CD / chemistry
Antigens, CD / genetics*
Antigens, CD / immunology
Binding Sites
Cell Line, Tumor
Chlorocebus aethiops
Endoplasmic Reticulum / genetics
Endoplasmic Reticulum / immunology
Endoplasmic Reticulum / virology
GPI-Linked Proteins / chemistry
GPI-Linked Proteins / genetics
GPI-Linked Proteins / immunology
Gene Expression Regulation
Golgi Apparatus / genetics
Golgi Apparatus / immunology
Golgi Apparatus / virology
HEK293 Cells
Host-Pathogen Interactions / genetics*
Host-Pathogen Interactions / immunology
Humans
Immunity, Innate
Interferon Regulatory Factors / classification
Interferon Regulatory Factors / genetics*
Interferon Regulatory Factors / immunology
Interferon Type I / genetics*
Interferon Type I / immunology
Molecular Docking Simulation
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
SARS-CoV-2 / genetics*
SARS-CoV-2 / immunology
Signal Transduction
Vero Cells
Viral Proteins / chemistry
Viral Proteins / genetics*
Viral Proteins / immunology
Virus Internalization
Virus Release / genetics
Virus Release / immunology
Virus Replication / genetics
Virus Replication / immunology

Substances

Antigens, CD
BST2 protein, human
GPI-Linked Proteins
Interferon Regulatory Factors
Interferon Type I
ORF7a protein, SARS-CoV-2
Viral Proteins

Associated data

GEO/GSE156295

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding