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

Scott B. Biering; Sylvia A. Sarnik; Eleanor Wang; James R. Zengel; Sarah R. Leist; Alexandra Schäfer; Varun Sathyan; Padraig Hawkins; Kenichi Okuda; Cyrus Tau; Aditya R. Jangid; Connor V. Duffy; Jin Wei; Rodney C. Gilmore; Mia Madel Alfajaro; Madison S. Strine; Xammy Nguyenla; Erik Van Dis; Carmelle Catamura; Livia H. Yamashiro; Julia A. Belk; Adam Begeman; Jessica C. Stark; D. Judy Shon; Douglas M. Fox; Shahrzad Ezzatpour; Emily Huang; Nico Olegario; Arjun Rustagi; Allison S. Volmer; Alessandra Livraghi-Butrico; Eddie Wehri; Richard R. Behringer; Dong Joo Cheon; Julia Schaletzky; Hector C. Aguilar; Andreas S. Puschnik; Brian Button; Benjamin A. Pinsky; Catherine A. Blish; Ralph S. Baric; Wanda K. O’Neal; Carolyn R. Bertozzi; Craig B. Wilen; Richard C. Boucher; Jan E. Carette; Sarah A. Stanley; Eva Harris; Silvana Konermann; Patrick D. Hsu

doi:10.1038/s41588-022-01131-x

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

Scott B. Biering, Sylvia A. Sarnik, Eleanor Wang, James R. Zengel, Sarah R. Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R. Jangid, Connor V. Duffy, Jin Wei, Rodney C. Gilmore, Mia Madel Alfajaro, Madison S. Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H. YamashiroJulia A. Belk, Adam Begeman, Jessica C. Stark, D. Judy Shon, Douglas M. Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S. Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R. Behringer, Dong Joo Cheon, Julia Schaletzky, Hector C. Aguilar, Andreas S. Puschnik, Brian Button, Benjamin A. Pinsky, Catherine A. Blish, Ralph S. Baric, Wanda K. O’Neal, Carolyn R. Bertozzi, Craig B. Wilen, Richard C. Boucher, Jan E. Carette, Sarah A. Stanley, Eva Harris, Silvana Konermann, Patrick D. Hsu

Genetics

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1078-1089
Number of pages	12
Journal	Nature Genetics
Volume	54
Issue number	8
DOIs	https://doi.org/10.1038/s41588-022-01131-x
State	Published - Aug 2022

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Genetics

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Biering, S. B., Sarnik, S. A., Wang, E., Zengel, J. R., Leist, S. R., Schäfer, A., Sathyan, V., Hawkins, P., Okuda, K., Tau, C., Jangid, A. R., Duffy, C. V., Wei, J., Gilmore, R. C., Alfajaro, M. M., Strine, M. S., Nguyenla, X., Van Dis, E., Catamura, C., ... Hsu, P. D. (2022). Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection. Nature Genetics, 54(8), 1078-1089. https://doi.org/10.1038/s41588-022-01131-x

Biering, SB, Sarnik, SA, Wang, E, Zengel, JR, Leist, SR, Schäfer, A, Sathyan, V, Hawkins, P, Okuda, K, Tau, C, Jangid, AR, Duffy, CV, Wei, J, Gilmore, RC, Alfajaro, MM, Strine, MS, Nguyenla, X, Van Dis, E, Catamura, C, Yamashiro, LH, Belk, JA, Begeman, A, Stark, JC, Shon, DJ, Fox, DM, Ezzatpour, S, Huang, E, Olegario, N, Rustagi, A, Volmer, AS, Livraghi-Butrico, A, Wehri, E, Behringer, RR, Cheon, DJ, Schaletzky, J, Aguilar, HC, Puschnik, AS, Button, B, Pinsky, BA, Blish, CA, Baric, RS, O’Neal, WK, Bertozzi, CR, Wilen, CB, Boucher, RC, Carette, JE, Stanley, SA, Harris, E, Konermann, S & Hsu, PD 2022, 'Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection', Nature Genetics, vol. 54, no. 8, pp. 1078-1089. https://doi.org/10.1038/s41588-022-01131-x

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

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.",

author = "Biering, {Scott B.} and Sarnik, {Sylvia A.} and Eleanor Wang and Zengel, {James R.} and Leist, {Sarah R.} and Alexandra Sch{\"a}fer and Varun Sathyan and Padraig Hawkins and Kenichi Okuda and Cyrus Tau and Jangid, {Aditya R.} and Duffy, {Connor V.} and Jin Wei and Gilmore, {Rodney C.} and Alfajaro, {Mia Madel} and Strine, {Madison S.} and Xammy Nguyenla and {Van Dis}, Erik and Carmelle Catamura and Yamashiro, {Livia H.} and Belk, {Julia A.} and Adam Begeman and Stark, {Jessica C.} and Shon, {D. Judy} and Fox, {Douglas M.} and Shahrzad Ezzatpour and Emily Huang and Nico Olegario and Arjun Rustagi and Volmer, {Allison S.} and Alessandra Livraghi-Butrico and Eddie Wehri and Behringer, {Richard R.} and Cheon, {Dong Joo} and Julia Schaletzky and Aguilar, {Hector C.} and Puschnik, {Andreas S.} and Brian Button and Pinsky, {Benjamin A.} and Blish, {Catherine A.} and Baric, {Ralph S.} and O{\textquoteright}Neal, {Wanda K.} and Bertozzi, {Carolyn R.} and Wilen, {Craig B.} and Boucher, {Richard C.} and Carette, {Jan E.} and Stanley, {Sarah A.} and Eva Harris and Silvana Konermann and Hsu, {Patrick D.}",

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doi = "10.1038/s41588-022-01131-x",

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AU - Biering, Scott B.

AU - Sarnik, Sylvia A.

AU - Wang, Eleanor

AU - Zengel, James R.

AU - Leist, Sarah R.

AU - Schäfer, Alexandra

AU - Sathyan, Varun

AU - Hawkins, Padraig

AU - Okuda, Kenichi

AU - Tau, Cyrus

AU - Jangid, Aditya R.

AU - Duffy, Connor V.

AU - Wei, Jin

AU - Gilmore, Rodney C.

AU - Alfajaro, Mia Madel

AU - Strine, Madison S.

AU - Nguyenla, Xammy

AU - Van Dis, Erik

AU - Catamura, Carmelle

AU - Yamashiro, Livia H.

AU - Belk, Julia A.

AU - Begeman, Adam

AU - Stark, Jessica C.

AU - Shon, D. Judy

AU - Fox, Douglas M.

AU - Ezzatpour, Shahrzad

AU - Huang, Emily

AU - Olegario, Nico

AU - Rustagi, Arjun

AU - Volmer, Allison S.

AU - Livraghi-Butrico, Alessandra

AU - Wehri, Eddie

AU - Behringer, Richard R.

AU - Cheon, Dong Joo

AU - Schaletzky, Julia

AU - Aguilar, Hector C.

AU - Puschnik, Andreas S.

AU - Button, Brian

AU - Pinsky, Benjamin A.

AU - Blish, Catherine A.

AU - Baric, Ralph S.

AU - O’Neal, Wanda K.

AU - Bertozzi, Carolyn R.

AU - Wilen, Craig B.

AU - Boucher, Richard C.

AU - Carette, Jan E.

AU - Stanley, Sarah A.

AU - Harris, Eva

AU - Konermann, Silvana

AU - Hsu, Patrick D.

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

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