Role of microbiota-derived corisin in coagulation activation during SARS-CoV-2 infection

Tatsuki Tsuruga; Hajime Fujimoto; Taro Yasuma; Corina N D'Alessandro-Gabazza; Masaaki Toda; Toshiyuki Ito; Atsushi Tomaru; Haruko Saiki; Tomohito Okano; Manal A B Alhawsawi; Atsuro Takeshita; Kota Nishihama; Reoto Takei; Yasuhiro Kondoh; Isaac Cann; Esteban C Gabazza; Tetsu Kobayashi

doi:10.1016/j.jtha.2024.02.014

Role of microbiota-derived corisin in coagulation activation during SARS-CoV-2 infection

J Thromb Haemost. 2024 Mar 5:S1538-7836(24)00118-1. doi: 10.1016/j.jtha.2024.02.014. Online ahead of print.

Authors

Tatsuki Tsuruga¹, Hajime Fujimoto¹, Taro Yasuma², Corina N D'Alessandro-Gabazza³, Masaaki Toda⁴, Toshiyuki Ito¹, Atsushi Tomaru¹, Haruko Saiki¹, Tomohito Okano¹, Manal A B Alhawsawi⁵, Atsuro Takeshita⁶, Kota Nishihama⁷, Reoto Takei⁸, Yasuhiro Kondoh⁸, Isaac Cann⁹, Esteban C Gabazza¹⁰, Tetsu Kobayashi¹¹

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan.
² Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan; Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan; Microbiome Research Center, Mie University, Tsu, Mie, Japan; Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan.
³ Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan; Microbiome Research Center, Mie University, Tsu, Mie, Japan; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
⁴ Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan.
⁵ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA; Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, USA.
⁶ Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan; Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan.
⁷ Department of Diabetes, Endocrinology and Metabolism, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan.
⁸ Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Aichi, Japan.
⁹ Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA; Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois, USA; Department of Animal Science, University of Illinois Urbana-Champaign, Urbana, Illinois, USA; Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
¹⁰ Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan; Microbiome Research Center, Mie University, Tsu, Mie, Japan; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. Electronic address: gabazza@doc.medic.mie-u.ac.jp.
¹¹ Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan; Microbiome Research Center, Mie University, Tsu, Mie, Japan.

PMID: 38453025
DOI: 10.1016/j.jtha.2024.02.014

Abstract

Background: Coagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood.

Objectives: The present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection.

Methods: This cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin.

Results: COVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells.

Conclusion: The microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells.

Keywords: COVID-19; apoptosis; coagulation; corisin; inflammation; microbiota.