학술논문
Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection
Document Type
article
Author
Biering, Scott B; Sarnik, Sylvia A; Wang, Eleanor; Zengel, James R; Leist, Sarah R; Schäfer, Alexandra; Sathyan, Varun; Hawkins, Padraig; Okuda, Kenichi; Tau, Cyrus; Jangid, Aditya R; Duffy, Connor V; Wei, Jin; Gilmore, Rodney C; Alfajaro, Mia Madel; Strine, Madison S; Nguyenla, Xammy; Van Dis, Erik; Catamura, Carmelle; Yamashiro, Livia H; Belk, Julia A; Begeman, Adam; Stark, Jessica C; Shon, D Judy; Fox, Douglas M; Ezzatpour, Shahrzad; Huang, Emily; Olegario, Nico; Rustagi, Arjun; Volmer, Allison S; Livraghi-Butrico, Alessandra; Wehri, Eddie; Behringer, Richard R; Cheon, Dong-Joo; Schaletzky, Julia; Aguilar, Hector C; Puschnik, Andreas S; Button, Brian; Pinsky, Benjamin A; Blish, Catherine A; Baric, Ralph S; O’Neal, Wanda K; Bertozzi, Carolyn R; Wilen, Craig B; Boucher, Richard C; Carette, Jan E; Stanley, Sarah A; Harris, Eva; Konermann, Silvana; Hsu, Patrick D
Source
Nature Genetics. 54(8)
Subject
Language
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.