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

Abstract

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.

Keywords

Affiliated Institutions

• University of California, Berkeley US
• Palo Alto Institute US
• Arc Research Institute
• Innovative Genomics Institute US
• Stanford University US
• Lung Institute US
• Yale University US
• Albany Medical Center Hospital US
• Yale Cancer Center US
• The University of Texas MD Anderson Cancer Center US
• Cornell University US
• Howard Hughes Medical Institute US
• University of North Carolina at Chapel Hill US
• Chan Zuckerberg Initiative (United States) US

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