Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry
- Weill Cornell Medical College, United States
- TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Germany
- Cornell University, United States
- The Rockefeller University, United States
- Weill Cornell Medicine, United States
- 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.
Data availability
All new plasmids will be made available through Addgene.
Article and author information
Author details
Edward R Kastenhuber
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
- Jos W van der Meer, Radboud University Medical Centre, Netherlands
Version history
- Preprint posted: April 1, 2021 (view preprint)
- Received: February 8, 2022
- Accepted: February 22, 2022
- Accepted Manuscript published: March 16, 2022 (version 1)
- 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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Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry
eLife 11:e77444.
https://doi.org/10.7554/eLife.77444
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