Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection.

Animals COVID-19 / genetics Clustered Regularly Interspaced Short Palindromic Repeats Epigenesis, Genetic Humans Mice Mucins / genetics SARS-CoV-2

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
08 2022
Historique:
received: 21 05 2021
accepted: 10 06 2022
pubmed: 26 7 2022
medline: 10 8 2022
entrez: 25 7 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-022-01131-x PMID: 35879412 PMC: PMC9355872
pubmed: 35879412
doi: 10.1038/s41588-022-01131-x
pii: 10.1038/s41588-022-01131-x
pmc: PMC9355872
doi:

Substances chimiques

Mucins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1078-1089

Subventions

Organisme : NIAID NIH HHS
ID : K08 AI163369
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI156731
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL110873
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL125280
Pays : United States
Organisme : NIH HHS
ID : DP5 OD021369
Pays : United States
Organisme : NHLBI NIH HHS
ID : UH3 HL123645
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI109022
Pays : United States
Organisme : NIAID NIH HHS
ID : K08 AI128043
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI140186
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL108808
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK065988
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200423
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136961
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007502
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI157253
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI141970
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA250324
Pays : United States

Informations de copyright

© 2022. The Author(s).

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Auteurs

Scott B Biering (SB)

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0003-1991-629X

Sylvia A Sarnik (SA)

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0002-0466-5806

Eleanor Wang (E)

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.

James R Zengel (JR)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.

Sarah R Leist (SR)

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Alexandra Schäfer (A)

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
ORCID: 0000-0002-4760-4923

Varun Sathyan (V)

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0001-7929-4344

Padraig Hawkins (P)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Kenichi Okuda (K)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
ORCID: 0000-0001-9341-2730

Cyrus Tau (C)

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0001-7462-5431

Aditya R Jangid (AR)

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.

Connor V Duffy (CV)

Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.

Jin Wei (J)

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
ORCID: 0000-0002-2832-1610

Rodney C Gilmore (RC)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Mia Madel Alfajaro (MM)

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.

Madison S Strine (MS)

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.

Xammy Nguyenla (X)

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.

Erik Van Dis (E)

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Carmelle Catamura (C)

Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA.

Livia H Yamashiro (LH)

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Julia A Belk (JA)

Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.

Adam Begeman (A)

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0001-5458-8610

Jessica C Stark (JC)

Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA, USA.
ORCID: 0000-0003-3828-5438

D Judy Shon (DJ)

Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA, USA.

Douglas M Fox (DM)

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Shahrzad Ezzatpour (S)

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

Emily Huang (E)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Nico Olegario (N)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Arjun Rustagi (A)

Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0002-6921-1012

Allison S Volmer (AS)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Alessandra Livraghi-Butrico (A)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Eddie Wehri (E)

The Henry Wheeler Center for Emerging and Neglected Diseases, Berkeley, CA, USA.

Richard R Behringer (RR)

Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Dong-Joo Cheon (DJ)

Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, USA.

Julia Schaletzky (J)

The Henry Wheeler Center for Emerging and Neglected Diseases, Berkeley, CA, USA.
ORCID: 0000-0002-7437-4684

Hector C Aguilar (HC)

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

Andreas S Puschnik (AS)

Chan Zuckerberg Biohub, San Francisco, CA, USA.

Brian Button (B)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Benjamin A Pinsky (BA)

Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0001-8751-4810

Catherine A Blish (CA)

Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.
ORCID: 0000-0001-6946-7627

Ralph S Baric (RS)

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
ORCID: 0000-0001-6827-8701

Wanda K O'Neal (WK)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Carolyn R Bertozzi (CR)

Department of Chemistry and Stanford ChEM-H, Stanford University, Stanford, CA, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
ORCID: 0000-0003-4482-2754

Craig B Wilen (CB)

Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
ORCID: 0000-0003-2495-9403

Richard C Boucher (RC)

Marsico Lung Institute and Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Jan E Carette (JE)

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0002-5187-8070

Sarah A Stanley (SA)

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Eva Harris (E)

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. eharris@berkeley.edu.
ORCID: 0000-0002-7238-4037

Silvana Konermann (S)

Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA. silvanak@stanford.edu.
Arc Institute, Palo Alto, CA, USA. silvanak@stanford.edu.
ORCID: 0000-0001-7915-1685

Patrick D Hsu (PD)

Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA. pdhsu@berkeley.edu.
Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA. pdhsu@berkeley.edu.
Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA. pdhsu@berkeley.edu.
Arc Institute, Palo Alto, CA, USA. pdhsu@berkeley.edu.
ORCID: 0000-0002-9380-2648

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées en tandem › Clustered regularly interspaced short palindromic repeats › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Glycoprotéines › Mucoprotéines › Mucines › Genome-wide bidirectional CRISPR screens...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › Genome-wide bidirectional CRISPR screens...