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

View ORCID ProfileScott B. Biering, View ORCID ProfileSylvia A. Sarnik, Eleanor Wang, View ORCID ProfileJames R. Zengel, Varun Sathyan, View ORCID ProfileXammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H. Yamashiro, View ORCID ProfileAdam Begeman, Jessica C. Stark, View ORCID ProfileD. Judy Shon, Douglas M. Fox, View ORCID ProfileAndreas S. Puschnik, View ORCID ProfileCarolyn R. Bertozzi, View ORCID ProfileJan E. Carette, View ORCID ProfileSarah A. Stanley, Eva Harris, View ORCID ProfileSilvana Konermann, View ORCID ProfilePatrick D. Hsu
doi: https://doi.org/10.1101/2021.04.22.440848
Scott B. Biering
1Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
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  • ORCID record for Scott B. Biering
Sylvia A. Sarnik
2Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA
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  • ORCID record for Sylvia A. Sarnik
Eleanor Wang
2Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA
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James R. Zengel
4Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
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  • ORCID record for James R. Zengel
Varun Sathyan
2Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA
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Xammy Nguyenla
1Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
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Erik Van Dis
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
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Carmelle Catamura
6Center for Computational Biology, University of California, Berkeley, CA, USA
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Livia H. Yamashiro
1Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
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Adam Begeman
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
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Jessica C. Stark
7Department of Chemistry and Stanford ChEM-H, Stanford University School of Medicine, Stanford, CA, USA
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D. Judy Shon
7Department of Chemistry and Stanford ChEM-H, Stanford University School of Medicine, Stanford, CA, USA
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  • ORCID record for D. Judy Shon
Douglas M. Fox
1Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
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Andreas S. Puschnik
8Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA
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Carolyn R. Bertozzi
7Department of Chemistry and Stanford ChEM-H, Stanford University School of Medicine, Stanford, CA, USA
9Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
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Jan E. Carette
4Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA, USA
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  • ORCID record for Jan E. Carette
Sarah A. Stanley
1Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
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Eva Harris
1Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
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  • For correspondence: eharris@berkeley.edu silvanak@stanford.edu pdhsu@berkeley.edu
Silvana Konermann
10Department of Biochemistry, Stanford University, Stanford, CA, USA
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  • For correspondence: eharris@berkeley.edu silvanak@stanford.edu pdhsu@berkeley.edu
Patrick D. Hsu
2Department of Bioengineering, University of California, Berkeley, Berkeley, CA, USA
3Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA
6Center for Computational Biology, University of California, Berkeley, CA, USA
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  • For correspondence: eharris@berkeley.edu silvanak@stanford.edu pdhsu@berkeley.edu
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SUMMARY

SARS-CoV-2 can cause a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of the host factors mediating viral infection or restriction is critical to elucidate SARS-CoV-2 host-pathogen interactions and the progression of COVID-19. To this end, 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. These screens uncovered proviral and antiviral host factors across highly interconnected host pathways, including components implicated in 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. We demonstrate that multiple membrane-anchored mucins are critical inhibitors of SARS-CoV-2 entry and are upregulated in response to viral infection. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and suggests interactions between SARS-CoV-2 and airway mucins of COVID-19 patients as a host defense mechanism.

Competing Interest Statement

P.D.H. is a cofounder of Spotlight Therapeutics and Moment Biosciences and serves on the board of directors and scientific advisory boards, and is a scientific advisory board member to Vial Health and Serotiny. P.D.H. and S.K. are inventors on patents relating to CRISPR technologies. C.R.B. is a co-founder and Scientific Advisory Board member of Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), and InterVenn Bio, and a member of the Board of Directors of Eli Lily & Company.

Footnotes

  • ↵11 Lead contact

  • https://doi.org/10.1016/j.cell.2020.04.026

  • https://doi.org/10.1016/j.stem.2020.10.005

  • https://doi.org/10.1038/s41590-020-0778-2

  • https://doi.org/10.1016/j.immuni.2021.01.017

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145926

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3660650

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 23, 2021.
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Genome-wide, bidirectional CRISPR screens identify mucins as critical host factors modulating SARS-CoV-2 infection
Scott B. Biering, Sylvia A. Sarnik, Eleanor Wang, James R. Zengel, Varun Sathyan, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H. Yamashiro, Adam Begeman, Jessica C. Stark, D. Judy Shon, Douglas M. Fox, Andreas S. Puschnik, Carolyn R. Bertozzi, Jan E. Carette, Sarah A. Stanley, Eva Harris, Silvana Konermann, Patrick D. Hsu
bioRxiv 2021.04.22.440848; doi: https://doi.org/10.1101/2021.04.22.440848
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Genome-wide, bidirectional CRISPR screens identify mucins as critical host factors modulating SARS-CoV-2 infection
Scott B. Biering, Sylvia A. Sarnik, Eleanor Wang, James R. Zengel, Varun Sathyan, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H. Yamashiro, Adam Begeman, Jessica C. Stark, D. Judy Shon, Douglas M. Fox, Andreas S. Puschnik, Carolyn R. Bertozzi, Jan E. Carette, Sarah A. Stanley, Eva Harris, Silvana Konermann, Patrick D. Hsu
bioRxiv 2021.04.22.440848; doi: https://doi.org/10.1101/2021.04.22.440848

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