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. WhelanPaul S. Keim, Bridget Marie Barker, Michael A. Caligiuri, Jianhua Yu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Article number1936
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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