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SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

53 Pages Posted: 17 Aug 2020 Publication Status: Published

See all articles by Thomas Mandel Clausen

Thomas Mandel Clausen

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Daniel R. Sandoval

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Charlotte B. Spliid

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Jessica Pihl

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Chelsea D. Painter

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Bryan E. Thacker

TEGA Therapeutics

Charles A. Glass

TEGA Therapeutics

Anoop Narayanan

Pennsylvania State University - Department of Biochemistry and Molecular Biology

Sydney A. Majowicz

Pennsylvania State University - Department of Biochemistry and Molecular Biology

Yang Zhang

University of Copenhagen - Copenhagen Center for Glycomics

Jonathan L. Torres

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Gregory J. Golden

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Ryan Porell

University of California, San Diego (UCSD) - Department of Chemistry and Biochemistry

Aaron F. Garretson

University of California, San Diego (UCSD) - Department of Medicine

Logan Laubach

University of California, San Diego (UCSD) - Department of Chemistry and Biochemistry

Jared Feldman

Ragon Institute of MGH, MIT and Harvard

Xin Yin

Sanford Burnham Prebys Medical Discovery Institute - Immunity and Pathogenesis Program

Yuan Pu

Sanford Burnham Prebys Medical Discovery Institute - Immunity and Pathogenesis Program

Blake M. Hauser

Ragon Institute of MGH, MIT and Harvard

Timothy M. Caradonna

Ragon Institute of MGH, MIT and Harvard

Benjamin P. Kellman

University of California, San Diego (UCSD) - Department of Bioengineering

Cameron Martino

University of California, San Diego (UCSD) - Department of Bioengineering

Philip L.S.M. Gordts

University of California, San Diego (UCSD) - Department of Medicine

Sandra L. Leibel

University of California, San Diego (UCSD) - Department of Pediatrics

Summit K. Chanda

Sanford Burnham Prebys Medical Discovery Institute - Immunity and Pathogenesis Program

Aaron Schmidt

Ragon Institute of MGH, MIT and Harvard

Kamil Godula

University of California, San Diego (UCSD) - Department of Chemistry and Biochemistry

Joyce Jose

Pennsylvania State University - Department of Biochemistry and Molecular Biology

Kevin D. Corbett

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

Andrew B. Ward

The Scripps Research Institute - Department of Integrative Structural and Computational Biology; The Scripps Research Institute - Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; The Scripps Research Institute - IAVI Neutralizing Antibody Center

Aaron F. Carlin

University of California, San Diego (UCSD) - Department of Medicine

Jeffrey D. Esko

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine

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Abstract

We show that SARS-CoV-2 spike protein interacts with cell surface heparan sulfate and angiotensin converting enzyme 2 (ACE2) through its Receptor Binding Domain. Docking studies suggest a putative heparin/heparan sulfate-binding site adjacent to the domain that binds to ACE2. In vitro, binding of ACE2 and heparin to spike protein ectodomains occurs independently and a ternary complex can be generated using heparin as a template. Contrary to studies with purified components, spike protein binding to heparan sulfate and ACE2 on cells occurs codependently. Unfractionated heparin, non-anticoagulant heparin, treatment with heparin lyases, and purified lung heparan sulfate potently block spike protein binding and infection by spike protein-pseudotyped virus and SARS-CoV-2 virus. These findings support a model for SARS-CoV-2 infection in which viral attachment and infection involves formation of a complex between heparan sulfate and ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin may represent new therapeutic opportunities.

Funding: This work was supported by RAPID grant 2031989 from the National Science Foundation and Project 3 of NIH P01 HL131474 to J.D.E.; The Alfred Benzon Foundation to T.M.C; NIH R01 AI146779 and a Massachusetts Consortium on Pathogenesis Readiness MassCPR grant to A.G.S.; DOD grant W81XWH-20-1-0270 and Fluomics/NOSI U19 AI135972 to S.K.C; a Career Award for Medical Scientists from the Burroughs Wellcome Fund to A.F.C.; Bill and Melinda Gates Foundation grant OPP1170236 to A.B.W.; COVID19 seed funding from the Huck Institutes of the Life Sciences and Penn State start-up funds to J.J.; and T32 training grants GM007753 for B.M.H. and T.C and AI007245 for J.F.; J.P. received funding from the Innovation Fund Denmark and VAR2 Pharmaceuticals.

Conflict of Interest: J.D.E. is a co-founder of TEGA Therapeutics. J.D.E. and The Regents of the University of California have licensed a University invention to and have an equity interest in TEGA Therapeutics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. C.A.G and B.E.T are employees of TEGA Therapeutics.

Ethical Approval: The collection of human tissue in this study abided by the Helsinki Principles. This work included postmortem human tissue, collected at the University Hospital, at the University of Copenhagen in Denmark. The patient provided informed consent for the tissue to be used for research purposes. All samples were completely deidentified before transfer to the researchers and this did not need specific IRB approval.

Keywords: COVID-19, SARS-CoV-2, Coronavirus, Spike proteins, Heparin,Heparan Sulfate,Pseudotype virus

Suggested Citation

Clausen, Thomas Mandel and Sandoval, Daniel R. and Spliid, Charlotte B. and Pihl, Jessica and Painter, Chelsea D. and Thacker, Bryan E. and Glass, Charles A. and Narayanan, Anoop and Majowicz, Sydney A. and Zhang, Yang and Torres, Jonathan L. and Golden, Gregory J. and Porell, Ryan and Garretson, Aaron F. and Laubach, Logan and Feldman, Jared and Yin, Xin and Pu, Yuan and Hauser, Blake M. and Caradonna, Timothy M. and Kellman, Benjamin P. and Martino, Cameron and Gordts, Philip L.S.M. and Leibel, Sandra L. and Chanda, Summit K. and Schmidt, Aaron and Godula, Kamil and Jose, Joyce and Corbett, Kevin D. and Ward, Andrew B. and Carlin, Aaron F. and Esko, Jeffrey D., SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Available at SSRN: https://ssrn.com/abstract=3657535 or http://dx.doi.org/10.2139/ssrn.3657535
This version of the paper has not been formally peer reviewed.

Thomas Mandel Clausen

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Daniel R. Sandoval

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Charlotte B. Spliid

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Jessica Pihl

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Chelsea D. Painter

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Bryan E. Thacker

TEGA Therapeutics ( email )

Charles A. Glass

TEGA Therapeutics ( email )

Anoop Narayanan

Pennsylvania State University - Department of Biochemistry and Molecular Biology ( email )

University Park
State College, PA 16802
United States

Sydney A. Majowicz

Pennsylvania State University - Department of Biochemistry and Molecular Biology ( email )

University Park
State College, PA 16802
United States

Yang Zhang

University of Copenhagen - Copenhagen Center for Glycomics ( email )

Nørregade 10
Copenhagen, København DK-1165
Denmark

Jonathan L. Torres

The Scripps Research Institute - Department of Integrative Structural and Computational Biology ( email )

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Gregory J. Golden

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Ryan Porell

University of California, San Diego (UCSD) - Department of Chemistry and Biochemistry ( email )

9500 Gilman Drive #0761
La Jolla, CA 92093-0761
United States

Aaron F. Garretson

University of California, San Diego (UCSD) - Department of Medicine ( email )

9500 Gilman Drive
La Jolla, CA 92093
United States

Logan Laubach

University of California, San Diego (UCSD) - Department of Chemistry and Biochemistry ( email )

9500 Gilman Drive #0761
La Jolla, CA 92093-0761
United States

Jared Feldman

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Xin Yin

Sanford Burnham Prebys Medical Discovery Institute - Immunity and Pathogenesis Program

10901 North Torrey Pines Road
La Jolla, CA
United States

Yuan Pu

Sanford Burnham Prebys Medical Discovery Institute - Immunity and Pathogenesis Program

10901 North Torrey Pines Road
La Jolla, CA
United States

Blake M. Hauser

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Timothy M. Caradonna

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Benjamin P. Kellman

University of California, San Diego (UCSD) - Department of Bioengineering ( email )

San Diego, CA 92093
United States

Cameron Martino

University of California, San Diego (UCSD) - Department of Bioengineering ( email )

San Diego, CA 92093
United States

Philip L.S.M. Gordts

University of California, San Diego (UCSD) - Department of Medicine ( email )

9500 Gilman Drive
La Jolla, CA 92093
United States

Sandra L. Leibel

University of California, San Diego (UCSD) - Department of Pediatrics ( email )

San Diego, CA 92093
United States

Summit K. Chanda

Sanford Burnham Prebys Medical Discovery Institute - Immunity and Pathogenesis Program ( email )

10901 North Torrey Pines Road
La Jolla, CA
United States

Aaron Schmidt

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Kamil Godula

University of California, San Diego (UCSD) - Department of Chemistry and Biochemistry ( email )

9500 Gilman Drive #0761
La Jolla, CA 92093-0761
United States

Joyce Jose

Pennsylvania State University - Department of Biochemistry and Molecular Biology

University Park
State College, PA 16802
United States

Kevin D. Corbett

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

Andrew B. Ward

The Scripps Research Institute - Department of Integrative Structural and Computational Biology ( email )

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

The Scripps Research Institute - Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery ( email )

La Jolla, CA
United States

The Scripps Research Institute - IAVI Neutralizing Antibody Center ( email )

La Jolla, CA
United States

Aaron F. Carlin

University of California, San Diego (UCSD) - Department of Medicine ( email )

9500 Gilman Drive
La Jolla, CA 92093
United States

Jeffrey D. Esko (Contact Author)

University of California, San Diego (UCSD) - Department of Cellular and Molecular Medicine ( email )

La Jolla, CA
United States

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