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

Nat Commun. 2023 Apr 6;14(1):1936. doi: 10.1038/s41467-023-37336-9.

Authors

Wenjuan Dong^#^{1

2}, Jing Wang^#^{1

2}, Lei Tian^#^{1

2}, Jianying Zhang³, Erik W Settles^{4

5}, Chao Qin⁶, Daniel R Steinken-Kollath⁴, Ashley N Itogawa⁴, Kimberly R Celona⁴, Jinhee Yi⁴, Mitchell Bryant⁴, Heather Mead⁴, Sierra A Jaramillo⁴, Hongjia Lu⁷, Aimin Li⁸, Ross E Zumwalt⁹, Sanjeet Dadwal¹⁰, Pinghui Feng⁶, Weiming Yuan⁷, Sean P J Whelan¹¹, Paul S Keim^{4

5}, Bridget Marie Barker^{4

5}, Michael A Caligiuri^{12

13

14}, Jianhua Yu^{15

16

17

18}

Affiliations

¹ Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
² Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
³ Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
⁴ Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ, 86011, USA.
⁵ Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ, 86011, USA.
⁶ Section of Infection and Immunity, Herman Ostrow School of Dentistry, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90089, USA.
⁷ Department of Molecular Microbiology and Immunology, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90033, USA.
⁸ Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
⁹ Department of Pathology, University of New Mexico, Albuquerque, NM, 87131, USA.
¹⁰ Division of Infectious Diseases, Department of Medicine, City of Hope National Medical Center, Los Angeles, CA, 91010, USA.
¹¹ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹² Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA. mcaligiuri@coh.org.
¹³ Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA. mcaligiuri@coh.org.
¹⁴ City of Hope Comprehensive Cancer Center, Los Angeles, CA, 91010, USA. mcaligiuri@coh.org.
¹⁵ Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, 91010, USA. jiayu@coh.org.
¹⁶ Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, 91010, USA. jiayu@coh.org.
¹⁷ City of Hope Comprehensive Cancer Center, Los Angeles, CA, 91010, USA. jiayu@coh.org.
¹⁸ Department of Immuno-Oncology, City of Hope, Los Angeles, CA, 91010, USA. jiayu@coh.org.

^# Contributed equally.

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.

Publication types

Research Support, U.S. Gov't, P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology
COVID-19*
Factor Xa*
Humans
Rivaroxaban / pharmacology
Rivaroxaban / therapeutic use
SARS-CoV-2 / metabolism
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism
Virus Internalization

Substances

Factor Xa
spike protein, SARS-CoV-2
Spike Glycoprotein, Coronavirus
Rivaroxaban
Antiviral Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding