TY - JOUR
T1 - Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection
AU - Dong, Wenjuan
AU - Wang, Jing
AU - Tian, Lei
AU - Zhang, Jianying
AU - Settles, Erik W.
AU - Qin, Chao
AU - Steinken-Kollath, Daniel R.
AU - Itogawa, Ashley N.
AU - Celona, Kimberly R.
AU - Yi, Jinhee
AU - Bryant, Mitchell
AU - Mead, Heather
AU - Jaramillo, Sierra A.
AU - Lu, Hongjia
AU - Li, Aimin
AU - Zumwalt, Ross E.
AU - Dadwal, Sanjeet
AU - Feng, Pinghui
AU - Yuan, Weiming
AU - Whelan, Sean P.J.
AU - Keim, Paul S.
AU - Barker, Bridget Marie
AU - Caligiuri, Michael A.
AU - Yu, Jianhua
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85151836154&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-37336-9
DO - 10.1038/s41467-023-37336-9
M3 - Article
C2 - 37024459
AN - SCOPUS:85151836154
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1936
ER -