Wenjuan Dong, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USAematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
Jing Wang, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USAematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
Lei Tian, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USAematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
Heather Mead, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA
Sierra A. Jaramillo, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA
Aimin Li, Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA
Ross E. Zumwalt, Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA
Sean P J Whelan, Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Erik W. Settles, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA
Paul S. Keim, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA
Bridget Marie Barker, Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA
Michael A. Caligiuri, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USAHematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USACity of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA
Jianhua Yu, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USAHematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USACity of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USADepartment of Immuno-Oncology, City of Hope, Los Angeles, CA 91010, USA
Jianying Zhang, Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA

Document Type

Article

Publication Date

6-8-2021

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human natural defense mechanisms against SARS-CoV-2 are largely unknown. Serine proteases (SPs) including furin and TMPRSS2 cleave SARS-CoV-2 spike protein, facilitating viral entry. Here, we show that FXa, a SP for blood coagulation, is upregulated in COVID-19 patients compared to non-COVID-19 donors and exerts anti-viral activity. Mechanistically, FXa cleaves the SARS-CoV-2 spike protein, which prevents its binding to ACE2, and thus blocks viral entry. Furthermore, the variant B.1.1.7 with several mutations is dramatically resistant to the anti-viral effect of FXa compared to wild-type SARA-CoV-2 in vivo and in vitro . The anti-coagulant rivaroxaban directly inhibits FXa and facilitates viral entry, whereas the indirect inhibitor fondaparinux does not. In a lethal humanized hACE2 mouse model of SARS-CoV-2, FXa prolonged survival while combination with rivaroxaban but not fondaparinux abrogated this protection. These preclinical results identify a previously unknown SP function and associated anti-viral host defense mechanism and suggest caution in considering direct inhibitors for prevention or treatment of thrombotic complications in COVID-19 patients.

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