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

Author

Listed:
  • Wenjuan Dong

    (City of Hope National Medical Center
    Hematologic Malignancies Research Institute, City of Hope National Medical Center)

  • Jing Wang

    (City of Hope National Medical Center
    Hematologic Malignancies Research Institute, City of Hope National Medical Center)

  • Lei Tian

    (City of Hope National Medical Center
    Hematologic Malignancies Research Institute, City of Hope National Medical Center)

  • Jianying Zhang

    (City of Hope National Medical Center)

  • Erik W. Settles

    (Northern Arizona University
    Northern Arizona University)

  • Chao Qin

    (University of Southern California)

  • Daniel R. Steinken-Kollath

    (Northern Arizona University)

  • Ashley N. Itogawa

    (Northern Arizona University)

  • Kimberly R. Celona

    (Northern Arizona University)

  • Jinhee Yi

    (Northern Arizona University)

  • Mitchell Bryant

    (Northern Arizona University)

  • Heather Mead

    (Northern Arizona University)

  • Sierra A. Jaramillo

    (Northern Arizona University)

  • Hongjia Lu

    (Keck School of Medicine of University of Southern California)

  • Aimin Li

    (Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center)

  • Ross E. Zumwalt

    (University of New Mexico)

  • Sanjeet Dadwal

    (City of Hope National Medical Center)

  • Pinghui Feng

    (University of Southern California)

  • Weiming Yuan

    (Keck School of Medicine of University of Southern California)

  • Sean P. J. Whelan

    (Washington University School of Medicine)

  • Paul S. Keim

    (Northern Arizona University
    Northern Arizona University)

  • Bridget Marie Barker

    (Northern Arizona University
    Northern Arizona University)

  • Michael A. Caligiuri

    (City of Hope National Medical Center
    Hematologic Malignancies Research Institute, City of Hope National Medical Center
    City of Hope Comprehensive Cancer Center)

  • Jianhua Yu

    (City of Hope National Medical Center
    Hematologic Malignancies Research Institute, City of Hope National Medical Center
    City of Hope Comprehensive Cancer Center
    City of Hope)

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.

Suggested Citation

  • 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 & S, 2023. "Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37336-9
    DOI: 10.1038/s41467-023-37336-9
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    as
    1. Erik Volz & Swapnil Mishra & Meera Chand & Jeffrey C. Barrett & Robert Johnson & Lily Geidelberg & Wes R. Hinsley & Daniel J. Laydon & Gavin Dabrera & Áine O’Toole & Robert Amato & Manon Ragonnet-Cron, 2021. "Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England," Nature, Nature, vol. 593(7858), pages 266-269, May.
    2. Bin Zhou & Tran Thi Nhu Thao & Donata Hoffmann & Adriano Taddeo & Nadine Ebert & Fabien Labroussaa & Anne Pohlmann & Jacqueline King & Silvio Steiner & Jenna N. Kelly & Jasmine Portmann & Nico Joel Ha, 2021. "SARS-CoV-2 spike D614G change enhances replication and transmission," Nature, Nature, vol. 592(7852), pages 122-127, April.
    3. Fatai S. Oladunni & Jun-Gyu Park & Paula A. Pino & Olga Gonzalez & Anwari Akhter & Anna Allué-Guardia & Angélica Olmo-Fontánez & Shalini Gautam & Andreu Garcia-Vilanova & Chengjin Ye & Kevin Chiem & C, 2020. "Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    4. Dami A. Collier & Anna Marco & Isabella A. T. M. Ferreira & Bo Meng & Rawlings P. Datir & Alexandra C. Walls & Steven A. Kemp & Jessica Bassi & Dora Pinto & Chiara Silacci-Fregni & Siro Bianchi & M. A, 2021. "Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies," Nature, Nature, vol. 593(7857), pages 136-141, May.
    5. Xiuyuan Ou & Yan Liu & Xiaobo Lei & Pei Li & Dan Mi & Lili Ren & Li Guo & Ruixuan Guo & Ting Chen & Jiaxin Hu & Zichun Xiang & Zhixia Mu & Xing Chen & Jieyong Chen & Keping Hu & Qi Jin & Jianwei Wang , 2020. "Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    6. Nicholas G. Davies & Christopher I. Jarvis & W. John Edmunds & Nicholas P. Jewell & Karla Diaz-Ordaz & Ruth H. Keogh, 2021. "Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7," Nature, Nature, vol. 593(7858), pages 270-274, May.
    7. Jessica A. Plante & Yang Liu & Jianying Liu & Hongjie Xia & Bryan A. Johnson & Kumari G. Lokugamage & Xianwen Zhang & Antonio E. Muruato & Jing Zou & Camila R. Fontes-Garfias & Divya Mirchandani & Dio, 2021. "Spike mutation D614G alters SARS-CoV-2 fitness," Nature, Nature, vol. 592(7852), pages 116-121, April.
    8. Yang Liu & Jianying Liu & Kenneth S. Plante & Jessica A. Plante & Xuping Xie & Xianwen Zhang & Zhiqiang Ku & Zhiqiang An & Dionna Scharton & Craig Schindewolf & Steven G. Widen & Vineet D. Menachery &, 2022. "The N501Y spike substitution enhances SARS-CoV-2 infection and transmission," Nature, Nature, vol. 602(7896), pages 294-299, February.
    9. Bryan A. Johnson & Xuping Xie & Adam L. Bailey & Birte Kalveram & Kumari G. Lokugamage & Antonio Muruato & Jing Zou & Xianwen Zhang & Terry Juelich & Jennifer K. Smith & Lihong Zhang & Nathen Bopp & C, 2021. "Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis," Nature, Nature, vol. 591(7849), pages 293-299, March.
    10. Aaron T. Irving & Matae Ahn & Geraldine Goh & Danielle E. Anderson & Lin-Fa Wang, 2021. "Lessons from the host defences of bats, a unique viral reservoir," Nature, Nature, vol. 589(7842), pages 363-370, January.
    11. Jessica A. Plante & Yang Liu & Jianying Liu & Hongjie Xia & Bryan A. Johnson & Kumari G. Lokugamage & Xianwen Zhang & Antonio E. Muruato & Jing Zou & Camila R. Fontes-Garfias & Divya Mirchandani & Dio, 2021. "Author Correction: Spike mutation D614G alters SARS-CoV-2 fitness," Nature, Nature, vol. 595(7865), pages 1-1, July.
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