微生物群衍生的 corisin 在 SARS-CoV-2 感染期间凝血激活中的作用。

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

机构信息

Department of Pulmonary and Critical Care Medicine, Faculty and Graduate School of Medicine, Mie University, Tsu, Mie, Japan.

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.

出版信息

J Thromb Haemost. 2024 Jul;22(7):1919-1935. doi: 10.1016/j.jtha.2024.02.014. Epub 2024 Mar 5.

DOI:10.1016/j.jtha.2024.02.014

PMID:38453025

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.

摘要

背景

凝血功能障碍是 COVID-19 患者发病和死亡的主要原因。COVID-19 中的高凝状态导致深静脉血栓形成、血栓栓塞并发症和弥漫性血管内凝血。微生物组失调会影响 COVID-19 的临床病程。然而，微生物组失调在 COVID-19 相关凝血功能障碍中的作用尚未完全阐明。

目的

本研究检验了以下假设，即微生物衍生的促凋亡蛋白 corisin 参与了 SARS-CoV-2 感染期间凝血系统的激活。

方法

这项横断面研究纳入了 47 例连续就诊的 COVID-19 症状患者。采用小鼠急性肺损伤模型来重现临床发现。使用 A549 肺泡上皮细胞、THP-1 和人脐静脉内皮细胞来评估 corisin 的促凝和抗凝活性。

结果

与健康受试者相比，COVID-19 患者的循环 corisin、凝血酶-抗凝血酶复合物、D-二聚体、肿瘤坏死因子-α和单核细胞趋化蛋白-1 水平显著升高，而游离蛋白 S 水平降低。凝血酶-抗凝血酶复合物、D-二聚体和 corisin 水平呈显著相关。单克隆抗 corisin 中和抗体可显著抑制 SARS-CoV-2 刺突蛋白相关急性肺损伤小鼠模型中的炎症反应和凝血系统激活，corisin 水平与凝血酶-抗凝血酶复合物水平显著相关。在体外实验中，corisin 增加了组织因子活性并降低了上皮细胞、内皮细胞和单核细胞中血栓调节蛋白的抗凝活性。