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

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Abstract

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.

Abstract

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 identify mucins as key host factors restricting viral infection.

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STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets

Damian Szklarczyk, Annika L Gable, David Lyon … (2018)

Abstract Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein–protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein–protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/.

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Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Xiaobo Yang, Yuan Yu, Jiqian Xu … (2020)

Summary Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. Funding None.

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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu … (2021)

Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

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Author and article information

Contributors

Eva Harris:

ORCID: http://orcid.org/0000-0002-7238-4037

eharris@berkeley.edu

Silvana Konermann:

ORCID: http://orcid.org/0000-0001-7915-1685

silvanak@stanford.edu

Patrick D. Hsu:

ORCID: http://orcid.org/0000-0002-9380-2648

pdhsu@berkeley.edu

Journal

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat Genet

Title: Nature Genetics

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date (Electronic): 25 July 2022

Publication date PMC-release: 25 July 2022

Publication date (Print): 2022

Volume: 54

Issue: 8

Pages: 1078-1089

Affiliations

[1 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Division of Infectious Diseases and Vaccinology, School of Public Health, , University of California, Berkeley, ; Berkeley, CA USA

[2 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Department of Bioengineering, , University of California, Berkeley, ; Berkeley, CA USA

[3 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Innovative Genomics Institute, , University of California, Berkeley, ; Berkeley, CA USA

[4 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Microbiology and Immunology, , Stanford University School of Medicine, ; Stanford, CA USA

[5 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Epidemiology, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA

[6 ]GRID grid.10698.36, ISNI 0000000122483208, Marsico Lung Institute and Cystic Fibrosis Research Center, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA

[7 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Biochemistry, , Stanford University School of Medicine, ; Stanford, CA USA

[8 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Laboratory Medicine, , Yale School of Medicine, ; New Haven, CT USA

[9 ]GRID grid.47100.32, ISNI 0000000419368710, Department of Immunobiology, , Yale School of Medicine, ; New Haven, CT USA

[10 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Department of Molecular and Cell Biology, , University of California, Berkeley, ; Berkeley, CA USA

[11 ]GRID grid.47840.3f, ISNI 0000 0001 2181 7878, Center for Computational Biology, , University of California, Berkeley, ; Berkeley, CA USA

[12 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Chemistry and Stanford ChEM-H, , Stanford University, ; Stanford, CA USA

[13 ]GRID grid.5386.8, ISNI 000000041936877X, Department of Microbiology and Immunology, College of Veterinary Medicine, , Cornell University, ; Ithaca, NY USA

[14 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Biochemistry and Biophysics, , University of North Carolina at Chapel Hill, ; Chapel Hill, NC USA

[15 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Medicine, Division of Infectious Diseases and Geographic Medicine, , Stanford University School of Medicine, ; Stanford, CA USA

[16 ]The Henry Wheeler Center for Emerging and Neglected Diseases, Berkeley, CA USA

[17 ]GRID grid.240145.6, ISNI 0000 0001 2291 4776, Department of Genetics, , University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[18 ]GRID grid.413558.e, ISNI 0000 0001 0427 8745, Department of Regenerative and Cancer Cell Biology, , Albany Medical College, ; Albany, NY USA

[19 ]GRID grid.499295.a, ISNI 0000 0004 9234 0175, Chan Zuckerberg Biohub, ; San Francisco, CA USA

[20 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Pathology, , Stanford University School of Medicine, ; Stanford, CA USA

[21 ]GRID grid.168010.e, ISNI 0000000419368956, Howard Hughes Medical Institute, , Stanford University, ; Stanford, CA USA

[22 ]GRID grid.47100.32, ISNI 0000000419368710, Yale Cancer Center, , Yale School of Medicine, ; New Haven, CT USA

[23 ]Arc Institute, Palo Alto, CA USA

Author information

Scott B. Biering http://orcid.org/0000-0003-1991-629X

Sylvia A. Sarnik http://orcid.org/0000-0002-0466-5806

Alexandra Schäfer http://orcid.org/0000-0002-4760-4923

Varun Sathyan http://orcid.org/0000-0001-7929-4344

Kenichi Okuda http://orcid.org/0000-0001-9341-2730

Cyrus Tau http://orcid.org/0000-0001-7462-5431

Jin Wei http://orcid.org/0000-0002-2832-1610

Adam Begeman http://orcid.org/0000-0001-5458-8610

Jessica C. Stark http://orcid.org/0000-0003-3828-5438

Arjun Rustagi http://orcid.org/0000-0002-6921-1012

Julia Schaletzky http://orcid.org/0000-0002-7437-4684

Benjamin A. Pinsky http://orcid.org/0000-0001-8751-4810

Catherine A. Blish http://orcid.org/0000-0001-6946-7627

Ralph S. Baric http://orcid.org/0000-0001-6827-8701

Carolyn R. Bertozzi http://orcid.org/0000-0003-4482-2754

Craig B. Wilen http://orcid.org/0000-0003-2495-9403

Jan E. Carette http://orcid.org/0000-0002-5187-8070

Eva Harris http://orcid.org/0000-0002-7238-4037

Silvana Konermann http://orcid.org/0000-0001-7915-1685

Patrick D. Hsu http://orcid.org/0000-0002-9380-2648

Article

Publisher ID: 1131

DOI: 10.1038/s41588-022-01131-x

PMC ID: 9355872

PubMed ID: 35879412

SO-VID: 7aa216ea-635b-4617-b07e-ae6e7074a5a8

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 May 2021

Date accepted : 10 June 2022

Funding

Funded by: FundRef https://doi.org/10.13039/100000060, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID);

Award ID: K08AI128043

Award ID: AI109022, R21 AI156731

Award ID: R01-AI157253

Award ID: UH3-HL123645, P01-HL110873, R01-HL136961 P01-HL108808

Award ID: R01 AI140186

Award Recipient : Shahrzad Ezzatpour Hector C. Aguilar Ralph S. Baric Richard C. Boucher Jan E. Carette Patrick D. Hsu

Funded by: FundRef https://doi.org/10.13039/100000861, Burroughs Wellcome Fund (BWF);

Award ID: Investigators in the Pathogenesis of Infectious Disease

Award Recipient : Jan E. Carette

Funded by: FundRef https://doi.org/10.13039/100011671, G. Harold and Leila Y. Mathers Foundation (G. Harold & Leila Y. Mathers Foundation);

Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);

Award ID: DP5OD021369

Award ID: 5T32 AI007502

Award Recipient : Arjun Rustagi Patrick D. Hsu

Funded by: Fast Grants, Ludwig Family Foundation

Funded by: FundRef https://doi.org/10.13039/100000897, Cystic Fibrosis Foundation (CF Foundation);

Award ID: HAWKIN21F0

Award ID: OKUDA20G0

Award ID: BUTTON09G0

Award ID: BOUCHE15R0

Award Recipient : Padraig Hawkins Kenichi Okuda Brian Button Richard C. Boucher

Funded by: FundRef https://doi.org/10.13039/100000001, National Science Foundation (NSF);

Award ID: DGE-1752814

Award Recipient : Erik Van Dis

Funded by: FundRef https://doi.org/10.13039/100011541, U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics);

Award ID: 1F32CA250324-01

Award Recipient : Jessica C. Stark

Funded by: FundRef https://doi.org/10.13039/100000048, American Cancer Society (American Cancer Society, Inc.);

Award ID: PF-20-143-01-LIB

Award Recipient : Jessica C. Stark

Funded by: FundRef https://doi.org/10.13039/100000005, U.S. Department of Defense (United States Department of Defense);

Award ID: W81XWH-21-1-0256

Award Recipient : D. Judy Shon

Funded by: Caring Together Research Fund

Funded by: Animal histopathology service was performed in the Animal Histopathology & Laboratory Medicine Core at the University of North Carolina, which is supported in part by an NCI Center Core Support Grant (5P30CA016086–41) to the UNC Lineberger Comprehensive Cancer Center.

Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);

Award ID: R01CA200423

Award Recipient : Carolyn R. Bertozzi

Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);

Award ID: P30-DK065988-13

Award Recipient : Richard C. Boucher

Funded by: North Carolina Policy Collaboratory at the University of North Carolina at Chapel Hill with funding from the North Carolina Coronavirus Relief Fund established and appropriated by the North Carolina General Assembly.

Funded by: Fast Grants

Funded by: FundRef https://doi.org/10.13039/100000011, Howard Hughes Medical Institute (HHMI);

Funded by: Howard Hughes Hanna Gray fellow and Chan Zuckerberg Biohub investigator

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ScienceOpen disciplines: Genetics

Keywords: sars-cov-2,functional genomics,virology

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ScienceOpen disciplines: Genetics

Keywords: sars-cov-2, functional genomics, virology

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

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Novel Coronavirus Disease COVID-19

Most cited references 78

STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

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