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; Jianhua Yu

doi:10.1038/s41467-023-37336-9

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

Biological Sciences

Research output: Contribution to journal › Article › peer-review

4 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 language	English (US)
Article number	1936
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37336-9
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Dong, W., Wang, J., Tian, L., Zhang, J., Settles, E. W., Qin, C., Steinken-Kollath, D. R., Itogawa, A. N., Celona, K. R., Yi, J., Bryant, M., Mead, H., Jaramillo, S. A., Lu, H., Li, A., Zumwalt, R. E., Dadwal, S., Feng, P., Yuan, W., ... Yu, J. (2023). Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection. Nature Communications, 14(1), Article 1936. https://doi.org/10.1038/s41467-023-37336-9

Dong, W, Wang, J, Tian, L, Zhang, J, Settles, EW, Qin, C, Steinken-Kollath, DR, Itogawa, AN, Celona, KR, Yi, J, Bryant, M, Mead, H, Jaramillo, SA, Lu, H, Li, A, Zumwalt, RE, Dadwal, S, Feng, P, Yuan, W, Whelan, SPJ, Keim, PS , Barker, BM, Caligiuri, MA & Yu, J 2023, 'Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection', Nature Communications, vol. 14, no. 1, 1936. https://doi.org/10.1038/s41467-023-37336-9

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title = "Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection",

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.",

author = "Wenjuan Dong and Jing Wang and Lei Tian and Jianying Zhang and Settles, {Erik W.} and Chao Qin and Steinken-Kollath, {Daniel R.} and Itogawa, {Ashley N.} and Celona, {Kimberly R.} and Jinhee Yi and Mitchell Bryant and Heather Mead and Jaramillo, {Sierra A.} and Hongjia Lu and Aimin Li and Zumwalt, {Ross E.} and Sanjeet Dadwal and Pinghui Feng and Weiming Yuan and Whelan, {Sean P.J.} and Keim, {Paul S.} and Barker, {Bridget Marie} and Caligiuri, {Michael A.} and Jianhua Yu",

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doi = "10.1038/s41467-023-37336-9",

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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

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.

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

Abstract

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