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

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  • Biering, S.B.
    • Other Affiliation: University of California, Berkeley
  • Sarnik, S.A.
    • Other Affiliation: University of California, Berkeley
  • Wang, E.
    • Other Affiliation: University of California, Berkeley
  • Zengel, J.R.
    • Other Affiliation: Stanford University School of Medicine
  • Leist, S.R.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Schäfer, A.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Sathyan, V.
    • Other Affiliation: University of California, Berkeley
  • Hawkins, P.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Okuda, K.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Tau, C.
    • Other Affiliation: University of California, Berkeley
  • Jangid, A.R.
    • Other Affiliation: University of California, Berkeley
  • Duffy, C.V.
    • Other Affiliation: Stanford University School of Medicine
  • Wei, J.
    • Other Affiliation: Yale School of Medicine
  • Gilmore, R.C.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Alfajaro, M.M.
    • Other Affiliation: Yale School of Medicine
  • Strine, M.S.
    • Other Affiliation: Yale School of Medicine
  • Nguyenla, X.
    • Other Affiliation: University of California, Berkeley
  • Van Dis, E.
    • Other Affiliation: University of California, Berkeley
  • Catamura, C.
    • Other Affiliation: University of California, Berkeley
  • Yamashiro, L.H.
    • Other Affiliation: University of California, Berkeley
  • Belk, J.A.
    • Other Affiliation: Stanford University School of Medicine
  • Begeman, A.
    • Other Affiliation: University of California, Berkeley
  • Stark, J.C.
    • Other Affiliation: Stanford University
  • Shon, D.J.
    • Other Affiliation: Stanford University
  • Fox, D.M.
    • Other Affiliation: University of California, Berkeley
  • Ezzatpour, S.
    • Other Affiliation: Cornell University
  • Huang, E.
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Olegario, N.
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Rustagi, A.
    • Other Affiliation: Stanford University School of Medicine
  • Volmer, A.S.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Livraghi-Butrico, A.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Wehri, E.
    • Other Affiliation: The Henry Wheeler Center for Emerging and Neglected Diseases
  • Behringer, R.R.
    • Other Affiliation: University of Texas MD Anderson Cancer Center
  • Cheon, D.-J.
    • Other Affiliation: Albany Medical College
  • Schaletzky, J.
    • Other Affiliation: The Henry Wheeler Center for Emerging and Neglected Diseases
  • Aguilar, H.C.
    • Other Affiliation: Cornell University
  • Puschnik, A.S.
    • Other Affiliation: Chan Zuckerberg Biohub
  • Button, B.
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
  • Pinsky, B.A.
    • Other Affiliation: Stanford University School of Medicine
  • Blish, C.A.
    • Other Affiliation: Stanford University School of Medicine
  • Baric, R.S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • O'Neal, W.K.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Bertozzi, C.R.
    • Other Affiliation: Stanford University
  • Wilen, C.B.
    • Other Affiliation: Yale School of Medicine
  • Boucher, R.C.
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Carette, J.E.
    • Other Affiliation: Stanford University School of Medicine
  • Stanley, S.A.
    • Other Affiliation: University of California, Berkeley
  • Harris, E.
    • Other Affiliation: University of California, Berkeley
  • Konermann, S.
    • Other Affiliation: Stanford University School of Medicine
  • Hsu, P.D.
    • Other Affiliation: University of California, Berkeley
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.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
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  • Nature Genetics
Language
  • English
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  • Publisher
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  • 1546-1718

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