Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry

  1. Edward R Kastenhuber
  2. Marisa Mercadante
  3. Benjamin Nilsson-Payant
  4. Jared L Johnson
  5. Javier A Jaimes
  6. Frauke Muecksch
  7. Yiska Weisblum
  8. Yaron Bram
  9. Gary R Whittaker
  10. Benjamin R tenOever
  11. Robert E Schwartz
  12. Vasuretha Chandar
  13. Lewis Cantley  Is a corresponding author
  1. Weill Cornell Medical College, United States
  2. TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Germany
  3. Cornell University, United States
  4. The Rockefeller University, United States
  5. Weill Cornell Medicine, United States
  6. New York University Langone Medical Center, United States

Abstract

Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases as well as coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.

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All new plasmids will be made available through Addgene.

Article and author information

Author details

  1. Edward R Kastenhuber

    Department of Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1872-212X
  2. Marisa Mercadante

    Department of Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  3. Benjamin Nilsson-Payant

    Institute of Experimental Virology, TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Hannover, Germany
    Competing interests
    No competing interests declared.
  4. Jared L Johnson

    Department of Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    No competing interests declared.
  5. Javier A Jaimes

    Department of Microbiology and Immunology, Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6706-092X
  6. Frauke Muecksch

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0132-5101
  7. Yiska Weisblum

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9249-1745
  8. Yaron Bram

    Department of Medicine, Weill Cornell Medicine, New York, United States
    Competing interests
    No competing interests declared.
  9. Gary R Whittaker

    Department of Microbiology and Immunology, Cornell University, Ithaca, United States
    Competing interests
    No competing interests declared.
  10. Benjamin R tenOever

    Department of Microbiology, New York University Langone Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  11. Robert E Schwartz

    Department of Medicine, Weill Cornell Medicine, New York, United States
    Competing interests
    Robert E Schwartz, is on the scientific advisory board for Miromatrix Inc and is a consultant and speaker for Alnylam Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5417-5995
  12. Vasuretha Chandar

    Department of Medicine, Weill Cornell Medicine, New York, United States
    Competing interests
    No competing interests declared.
  13. Lewis Cantley

    Department of Medicine, Weill Cornell Medical College, New York, United States
    For correspondence
    lcantley@med.cornell.edu
    Competing interests
    Lewis Cantley, is a founder and member of the SAB of Agios Pharmaceuticals and a founder and former member of the SAB of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals). These companies are developing novel therapies for cancer. Holds equity in Agios. Lewis Cantley's laboratory also received some financial support from Ravenna Pharmaceuticals..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1298-7653

Funding

National Institutes of Health (R01AI35270)

  • Gary R Whittaker

National Cancer Institute (R35CA197588)

  • Lewis Cantley

Pershing Square Foundation

  • Lewis Cantley

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jos W van der Meer, Radboud University Medical Centre, Netherlands

Version history

  1. Preprint posted: April 1, 2021 (view preprint)
  2. Received: February 8, 2022
  3. Accepted: February 22, 2022
  4. Accepted Manuscript published: March 16, 2022 (version 1)
  5. Version of Record published: March 23, 2022 (version 2)

Copyright

© 2022, Kastenhuber et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Edward R Kastenhuber
  2. Marisa Mercadante
  3. Benjamin Nilsson-Payant
  4. Jared L Johnson
  5. Javier A Jaimes
  6. Frauke Muecksch
  7. Yiska Weisblum
  8. Yaron Bram
  9. Gary R Whittaker
  10. Benjamin R tenOever
  11. Robert E Schwartz
  12. Vasuretha Chandar
  13. Lewis Cantley
(2022)
Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry
eLife 11:e77444.
https://doi.org/10.7554/eLife.77444

Share this article

https://doi.org/10.7554/eLife.77444

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    Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

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    Funding:

    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.