Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.
Angiotensin-Converting Enzyme 2
/ metabolism
Animals
COVID-19
/ immunology
Cell Line
Chlorocebus aethiops
Clustered Regularly Interspaced Short Palindromic Repeats
Coronavirus
/ classification
Coronavirus Infections
/ drug therapy
Gene Knockout Techniques
Gene Regulatory Networks
Genome-Wide Association Study
HEK293 Cells
HMGB1 Protein
/ genetics
Host-Pathogen Interactions
/ drug effects
Humans
SARS-CoV-2
/ physiology
Vero Cells
Virus Internalization
COVID-19
CRISPR screen
Epigenetics
HMGB1
MERS-CoV
Middle East Respiratory Syndrome
SARS-CoV-2
SWI/SNF complex
Severe Acute Respiratory Syndrome
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
received:
19
07
2020
revised:
11
09
2020
accepted:
15
10
2020
pubmed:
5
11
2020
medline:
16
1
2021
entrez:
4
11
2020
Statut:
ppublish
Résumé
Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.
Identifiants
pubmed: 33147444
pii: S0092-8674(20)31392-1
doi: 10.1016/j.cell.2020.10.028
pmc: PMC7574718
pii:
doi:
Substances chimiques
HMGB1 Protein
0
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
76-91.e13Subventions
Organisme : NIAID NIH HHS
ID : R01 AI123449
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007019
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007223
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30 HL149151
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148467
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI157835
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI54739
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA121974
Pays : United States
Organisme : NIAID NIH HHS
ID : K08 AI128043
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI087925
Pays : United States
Organisme : NIDA NIH HHS
ID : F31 DA054739
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI133524
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA193200
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK116666
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI154739
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA196530
Pays : United States
Commentaires et corrections
Type : UpdateOf
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests Yale University (C.B.W.) has a patent pending related to this work entitled “Compounds and Compositions for Treating, Ameliorating, and/or Preventing SARS-CoV-2 Infection and/or Complications Thereof.” Yale University has committed to rapidly executable non-exclusive royalty-free licenses to intellectual property rights for the purpose of making and distributing products to prevent, diagnose, and treat COVID-19 infection during the pandemic and for a short period thereafter. J.G.D. consults for Foghorn Therapeutics, Maze Therapeutics, Merck, Agios, and Pfizer. J.G.D. consults for and has equity in Tango Therapeutics. C.K. is the Scientific Founder, Board of Directors member, Scientific Advisory Board member, shareholder, and consultant for Foghorn Therapeutics, Inc. (Cambridge, MA).
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