Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection

Wenjuan Dong, Jing Wang, Lei Tian, Jianying Zhang, Erik W. Settles, Chao Qin, Daniel R. Steinken-Kollath, Ashley N. Itogawa, Kimberly R. Celona, Jinhee Yi, Mitchell Bryant, Heather Mead, Sierra A. Jaramillo, Hongjia Lu, Aimin Li, Ross E. Zumwalt, Sanjeet Dadwal, Pinghui Feng, Weiming Yuan, Sean P. J. Whelan, Paul S. Keim, Bridget Marie Barker, Michael A. Caligiuri () and Jianhua Yu ()
Additional contact information
Wenjuan Dong: City of Hope National Medical Center
Jing Wang: City of Hope National Medical Center
Lei Tian: City of Hope National Medical Center
Jianying Zhang: City of Hope National Medical Center
Erik W. Settles: Northern Arizona University
Chao Qin: University of Southern California
Daniel R. Steinken-Kollath: Northern Arizona University
Ashley N. Itogawa: Northern Arizona University
Kimberly R. Celona: Northern Arizona University
Jinhee Yi: Northern Arizona University
Mitchell Bryant: Northern Arizona University
Heather Mead: Northern Arizona University
Sierra A. Jaramillo: Northern Arizona University
Hongjia Lu: Keck School of Medicine of University of Southern California
Aimin Li: Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center
Ross E. Zumwalt: University of New Mexico
Sanjeet Dadwal: City of Hope National Medical Center
Pinghui Feng: University of Southern California
Weiming Yuan: Keck School of Medicine of University of Southern California
Sean P. J. Whelan: Washington University School of Medicine
Paul S. Keim: Northern Arizona University
Bridget Marie Barker: Northern Arizona University
Michael A. Caligiuri: City of Hope National Medical Center
Jianhua Yu: City of Hope National Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.

Date: 2023
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DOI: 10.1038/s41467-023-37336-9

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