FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant.
| العنوان: | FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant. |
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| المؤلفون: | Dong W; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA., Wang J; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA., Tian L; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA., Zhang J; Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA 91010, USA., Mead H; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA., Jaramillo SA; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA., Li A; Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA., Zumwalt RE; Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA., Whelan SPJ; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA., Settles EW; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA., Keim PS; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA., Barker BM; Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, AZ 86011, USA., Caligiuri MA; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA., Yu J; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA 91010, USA.; City of Hope Comprehensive Cancer Center, Los Angeles, CA 91010, USA.; Department of Immuno-Oncology, City of Hope, Los Angeles, CA 91010, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2021 Jun 08. Date of Electronic Publication: 2021 Jun 08. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | 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. Competing Interests: DECLARATION OF INTERESTS No author has a direct conflict of interest relevant to this research to declare. |
| معلومات مُعتمدة: | R01 AI129582 United States AI NIAID NIH HHS; R01 NS106170 United States NS NINDS NIH HHS; R21 CA223400 United States CA NCI NIH HHS; R01 CA068458 United States CA NCI NIH HHS; R35 CA210087 United States CA NCI NIH HHS; P01 CA163205 United States CA NCI NIH HHS; R37 CA068458 United States CA NCI NIH HHS; R01 CA247550 United States CA NCI NIH HHS |
| تواريخ الأحداث: | Date Created: 20210615 Latest Revision: 20231019 |
| رمز التحديث: | 20231020 |
| مُعرف محوري في PubMed: | PMC8202421 |
| DOI: | 10.1101/2021.06.07.447437 |
| PMID: | 34127969 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2021.06.07.447437 |
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