tetano
Editor, Senior Moderator
Nat Genet
. 2022 Jul 25.
doi: 10.1038/s41588-022-01131-x. Online ahead of print.
Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection
Scott B Biering[SUP] #[/SUP][SUP] 1 [/SUP], Sylvia A Sarnik[SUP] #[/SUP][SUP] 2 3 [/SUP], Eleanor Wang[SUP] 2 3 [/SUP], James R Zengel[SUP] 4 [/SUP], Sarah R Leist[SUP] 5 [/SUP], Alexandra Schäfer[SUP] 5 [/SUP], Varun Sathyan[SUP] 2 3 [/SUP], Padraig Hawkins[SUP] 6 [/SUP], Kenichi Okuda[SUP] 6 [/SUP], Cyrus Tau[SUP] 2 3 [/SUP], Aditya R Jangid[SUP] 2 3 [/SUP], Connor V Duffy[SUP] 7 [/SUP], Jin Wei[SUP] 8 9 [/SUP], Rodney C Gilmore[SUP] 6 [/SUP], Mia Madel Alfajaro[SUP] 8 9 [/SUP], Madison S Strine[SUP] 8 9 [/SUP], Xammy Nguyenla[SUP] 1 [/SUP], Erik Van Dis[SUP] 10 [/SUP], Carmelle Catamura[SUP] 11 [/SUP], Livia H Yamashiro[SUP] 1 10 [/SUP], Julia A Belk[SUP] 7 [/SUP], Adam Begeman[SUP] 10 [/SUP], Jessica C Stark[SUP] 12 [/SUP], D Judy Shon[SUP] 12 [/SUP], Douglas M Fox[SUP] 1 10 [/SUP], Shahrzad Ezzatpour[SUP] 13 [/SUP], Emily Huang[SUP] 6 14 [/SUP], Nico Olegario[SUP] 6 14 [/SUP], Arjun Rustagi[SUP] 15 [/SUP], Allison S Volmer[SUP] 6 [/SUP], Alessandra Livraghi-Butrico[SUP] 6 [/SUP], Eddie Wehri[SUP] 16 [/SUP], Richard R Behringer[SUP] 17 [/SUP], Dong-Joo Cheon[SUP] 18 [/SUP], Julia Schaletzky[SUP] 16 [/SUP], Hector C Aguilar[SUP] 13 [/SUP], Andreas S Puschnik[SUP] 19 [/SUP], Brian Button[SUP] 6 14 [/SUP], Benjamin A Pinsky[SUP] 15 20 [/SUP], Catherine A Blish[SUP] 15 19 [/SUP], Ralph S Baric[SUP] 5 [/SUP], Wanda K O'Neal[SUP] 6 [/SUP], Carolyn R Bertozzi[SUP] 12 21 [/SUP], Craig B Wilen[SUP] 8 9 22 [/SUP], Richard C Boucher[SUP] 6 [/SUP], Jan E Carette[SUP] 4 [/SUP], Sarah A Stanley[SUP] 1 10 [/SUP], Eva Harris[SUP] 23 [/SUP], Silvana Konermann[SUP] 24 25 [/SUP], Patrick D Hsu[SUP] 26 27 28 29 [/SUP]
Affiliations
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.
. 2022 Jul 25.
doi: 10.1038/s41588-022-01131-x. Online ahead of print.
Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection
Scott B Biering[SUP] #[/SUP][SUP] 1 [/SUP], Sylvia A Sarnik[SUP] #[/SUP][SUP] 2 3 [/SUP], Eleanor Wang[SUP] 2 3 [/SUP], James R Zengel[SUP] 4 [/SUP], Sarah R Leist[SUP] 5 [/SUP], Alexandra Schäfer[SUP] 5 [/SUP], Varun Sathyan[SUP] 2 3 [/SUP], Padraig Hawkins[SUP] 6 [/SUP], Kenichi Okuda[SUP] 6 [/SUP], Cyrus Tau[SUP] 2 3 [/SUP], Aditya R Jangid[SUP] 2 3 [/SUP], Connor V Duffy[SUP] 7 [/SUP], Jin Wei[SUP] 8 9 [/SUP], Rodney C Gilmore[SUP] 6 [/SUP], Mia Madel Alfajaro[SUP] 8 9 [/SUP], Madison S Strine[SUP] 8 9 [/SUP], Xammy Nguyenla[SUP] 1 [/SUP], Erik Van Dis[SUP] 10 [/SUP], Carmelle Catamura[SUP] 11 [/SUP], Livia H Yamashiro[SUP] 1 10 [/SUP], Julia A Belk[SUP] 7 [/SUP], Adam Begeman[SUP] 10 [/SUP], Jessica C Stark[SUP] 12 [/SUP], D Judy Shon[SUP] 12 [/SUP], Douglas M Fox[SUP] 1 10 [/SUP], Shahrzad Ezzatpour[SUP] 13 [/SUP], Emily Huang[SUP] 6 14 [/SUP], Nico Olegario[SUP] 6 14 [/SUP], Arjun Rustagi[SUP] 15 [/SUP], Allison S Volmer[SUP] 6 [/SUP], Alessandra Livraghi-Butrico[SUP] 6 [/SUP], Eddie Wehri[SUP] 16 [/SUP], Richard R Behringer[SUP] 17 [/SUP], Dong-Joo Cheon[SUP] 18 [/SUP], Julia Schaletzky[SUP] 16 [/SUP], Hector C Aguilar[SUP] 13 [/SUP], Andreas S Puschnik[SUP] 19 [/SUP], Brian Button[SUP] 6 14 [/SUP], Benjamin A Pinsky[SUP] 15 20 [/SUP], Catherine A Blish[SUP] 15 19 [/SUP], Ralph S Baric[SUP] 5 [/SUP], Wanda K O'Neal[SUP] 6 [/SUP], Carolyn R Bertozzi[SUP] 12 21 [/SUP], Craig B Wilen[SUP] 8 9 22 [/SUP], Richard C Boucher[SUP] 6 [/SUP], Jan E Carette[SUP] 4 [/SUP], Sarah A Stanley[SUP] 1 10 [/SUP], Eva Harris[SUP] 23 [/SUP], Silvana Konermann[SUP] 24 25 [/SUP], Patrick D Hsu[SUP] 26 27 28 29 [/SUP]
Affiliations
- PMID: 35879412
- DOI: 10.1038/s41588-022-01131-x
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.