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Systematic Genome-Scale Identification of Host Factors for SARS-CoV-2 Infection Across Models Yields a Core Single Gene Dependency; Ace2

51 Pages Posted: 2 Jul 2021 Publication Status: Review Complete

See all articles by Katherine Chan

Katherine Chan

University of Toronto - Donnelly Center

Adrian Granda Farias

University of Toronto - Donnelly Center

Hunsang Lee

University of Toronto - Donnelly Center

Furkan Guvenc

University of Toronto - Department of Molecular Genetics

Patricia Mero

University of Toronto - Donnelly Center

Kamaldeep Aulakh

University of Toronto - Donnelly Center

Kevin R. Brown

University of Toronto - Donnelly Center

Shahan Haider

University of Toronto - Donnelly Center

Edyta Marcon

University of Toronto - Donnelly Center

Ulrich Braunschweig

University of Toronto - Donnelly Center

Amy Hin Yan Tong

University of Toronto - Donnelly Center

Shuye Pu

University of Toronto - Donnelly Center

Andrea Habsid

University of Toronto - Donnelly Center

Natasha Chrsitie-Holmes

University of Toronto - Combined Containment Level 3 Unit

Patrick Budylowski

University of Toronto - Department of Molecular Genetics

Audrey Astori

Princess Margaret Cancer Center

Ayoob Ghalami

University of Toronto - Office of Environmental Health & Safety

Samira Mubareka

Sunnybrook Research Institute

Arinjay Banerjee

University of Saskatchewan - Vaccine and Infectious Disease Organization

Karen Mossman

McMaster University - Department of Pathology and Molecular Medicine

Jack Greenblatt

University of Toronto - Donnelly Center

Scott Gray-Owen

University of Toronto - Department of Molecular Genetics

Brian Raught

Princess Margaret Cancer Center

Benjamin Blencowe

University of Toronto - Donnelly Center

Mikko Taipale

University of Toronto - Donnelly Center

Jason Moffat

University of Toronto - Donnelly Center

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Abstract

SARS-CoV-2, depends on host cell components for replication, therefore the identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection. Such host factors may be necessary for infection and replication of SARS-CoV-2 and, if druggable, presents an attractive strategy for anti-viral therapy. We performed genome wide CRISPR knockout screens in Vero E6 cells and 4 human cell lines including Calu-3, Caco-2, Hek293 and Huh7 to identify genetic regulators of SARS-CoV-2 infection. Our findings identified only ACE2, the cognate SARS-CoV-2 entry receptor, as a common host dependency factor across all cell lines, while all other host genes identified were cell line specific including known factors TMPRSS2 and CTSL. Several of the discovered host-dependency factors converged on pathways involved in cell signalling, lipid metabolism, immune pathways and chromatin modulation. Notably, chromatin modulator genes KMT2C and KDM6A in Calu-3 cells had the strongest impact in preventing SARS-CoV-2 infection when perturbed. Overall, the network of host factors that have been identified will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate the development of host-directed therapies.

Funding Information: This work was supported by the University of Toronto COVID-19 Action Initiative Fund to J.M., B.J.B., S.G.O., J.G., K.M., and S.M.. Indirect support was also received from the University of Toronto and the Temerty Foundation to support enhanced capacity and operations of the Toronto Combined Containment Level 3 Facility during the COVID-19 pandemic. This work was also partially supported from a Canadian Institutes for Health Research Project Grant to J.M. (MOP142375). J.M. is a Tier 2 Canada Research Chair in Function Genomics.

Declaration of Interest: None to declare.

Suggested Citation

Chan, Katherine and Granda Farias, Adrian and Lee, Hunsang and Guvenc, Furkan and Mero, Patricia and Aulakh, Kamaldeep and Brown, Kevin R. and Haider, Shahan and Marcon, Edyta and Braunschweig, Ulrich and Tong, Amy Hin Yan and Pu, Shuye and Habsid, Andrea and Chrsitie-Holmes, Natasha and Budylowski, Patrick and Astori, Audrey and Ghalami, Ayoob and Mubareka, Samira and Banerjee, Arinjay and Mossman, Karen and Greenblatt, Jack and Gray-Owen, Scott and Raught, Brian and Blencowe, Benjamin and Taipale, Mikko and Moffat, Jason, Systematic Genome-Scale Identification of Host Factors for SARS-CoV-2 Infection Across Models Yields a Core Single Gene Dependency; Ace2. Available at SSRN: https://ssrn.com/abstract=3879085 or http://dx.doi.org/10.2139/ssrn.3879085
This version of the paper has not been formally peer reviewed.

Katherine Chan

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Adrian Granda Farias

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Hunsang Lee

University of Toronto - Donnelly Center

Furkan Guvenc

University of Toronto - Department of Molecular Genetics

105 St George Street
Toronto, M5S 3G8
Canada

Patricia Mero

University of Toronto - Donnelly Center ( email )

160 College Street, Room 230
Toronto
Canada

Kamaldeep Aulakh

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Kevin R. Brown

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Shahan Haider

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Edyta Marcon

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Ulrich Braunschweig

University of Toronto - Donnelly Center ( email )

160 College Street, Room 230
Toronto
Canada

Amy Hin Yan Tong

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Shuye Pu

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Andrea Habsid

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Natasha Chrsitie-Holmes

University of Toronto - Combined Containment Level 3 Unit ( email )

105 St George Street
Toronto, Ontario M5S 3G8
Canada

Patrick Budylowski

University of Toronto - Department of Molecular Genetics

105 St George Street
Toronto, M5S 3G8
Canada

Audrey Astori

Princess Margaret Cancer Center

105 St George Street
Toronto, M5S 3G8
Canada

Ayoob Ghalami

University of Toronto - Office of Environmental Health & Safety ( email )

105 St George Street
Toronto, Ontario M5S 3G8
Canada

Samira Mubareka

Sunnybrook Research Institute

Canada

Arinjay Banerjee

University of Saskatchewan - Vaccine and Infectious Disease Organization ( email )

College of Education
Saskatoon, Saskatchewan S7N 5A7
Canada

Karen Mossman

McMaster University - Department of Pathology and Molecular Medicine

Hamilton, Ontario
Canada

Jack Greenblatt

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Scott Gray-Owen

University of Toronto - Department of Molecular Genetics

105 St George Street
Toronto, M5S 3G8
Canada

Brian Raught

Princess Margaret Cancer Center ( email )

610 University Avenue
Toronto, ON M5G 2M9
Canada

Benjamin Blencowe

University of Toronto - Donnelly Center ( email )

160 College Street, Room 230
Toronto
Canada

Mikko Taipale

University of Toronto - Donnelly Center

105 St George Street
Toronto, M5S 3G8
Canada

Jason Moffat (Contact Author)

University of Toronto - Donnelly Center ( email )

160 College Street, Room 230
Toronto
Canada

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