循环细胞外囊泡在 SARS-CoV-2 感染中具有增强的促凝活性。
Circulating extracellular vesicles are endowed with enhanced procoagulant activity in SARS-CoV-2 infection.
机构信息
Laboratory of Cellular and Molecular Cardiology, Istituto Cardiocentro Ticino, Ente Ospedaliero Cantonale, Lugano, Switzerland; Center for Molecular Cardiology, Zurich, Switzerland.
Laboratory for Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Ente Ospedaliero Cantonale Lugano, Switzerland.
出版信息
EBioMedicine. 2021 May;67:103369. doi: 10.1016/j.ebiom.2021.103369. Epub 2021 May 7.
BACKGROUND
Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents.
METHODS
We analyzed serum-derived EV from 67 participants who underwent nasopharyngeal swabs molecular test for suspected SARS-CoV-2 infection (34 positives and 33 negatives) and from 16 healthy controls (HC), as referral. A sub-analysis was performed on subjects who developed pneumonia (n = 28). Serum-derived EV were characterized for their surface antigen profile and tested for their procoagulant activity. A validation experiment was performed pre-treating EV with anti-CD142 antibody or with recombinant FVIIa. Serum TNF-α levels were measured by ELISA.
FINDINGS
Profiling of EV antigens revealed a surface marker signature that defines circulating EV in COVID-19. A combination of seven surface molecules (CD49e, CD209, CD86, CD133/1, CD69, CD142, and CD20) clustered COVID (+) versus COVID (-) patients and HC. CD142 showed the highest discriminating performance at both multivariate models and ROC curve analysis. Noteworthy, we found that CD142 exposed onto surface of EV was biologically active. CD142 activity was higher in COVID (+) patients and correlated with TNF-α serum levels.
INTERPRETATION
In SARS-CoV-2 infection the systemic inflammatory response results in cell-release of substantial amounts of procoagulant EV that may act as clotting initiation agents, contributing to disease severity.
FUNDING
Cardiocentro Ticino Institute, Ente ospedaliero Cantonale, Lugano-Switzerland.
背景
冠状病毒 2（SARS-CoV-2）感染会引起急性呼吸系统综合征，伴有多器官损伤，提示存在促凝状态，导致广泛的微血管血栓形成。这种凝血异常的原因尚不清楚。组织因子受体，也称为 CD142，通常与细胞释放的细胞外囊泡（EV）有关。在这项研究中，我们旨在描述 COVID-19 患者循环 EV 的表面抗原谱，并研究其作为促凝剂的潜在作用。
方法
我们分析了 67 名接受鼻咽拭子分子检测疑似 SARS-CoV-2 感染的参与者（34 例阳性和 33 例阴性）和 16 名健康对照（HC）的血清来源 EV，其中亚组分析了发生肺炎的患者（n=28）。对 EV 的表面抗原谱进行了特征分析，并对其促凝活性进行了检测。用抗 CD142 抗体或重组 FVIIa 预处理 EV 进行了验证实验。通过 ELISA 测量血清 TNF-α 水平。
发现
EV 抗原谱分析揭示了一种定义 COVID-19 循环 EV 的表面标志物特征。七种表面分子（CD49e、CD209、CD86、CD133/1、CD69、CD142 和 CD20）的组合将 COVID（+）患者与 COVID（-）患者和 HC 患者区分开来。在多变量模型和 ROC 曲线分析中，CD142 显示出最高的区分性能。值得注意的是，我们发现暴露在 EV 表面的 CD142 具有生物学活性。COVID（+）患者的 CD142 活性更高，并与 TNF-α 血清水平相关。
解释
在 SARS-CoV-2 感染中，全身炎症反应导致大量促凝 EV 从细胞中释放，可能作为凝血起始剂，导致疾病严重程度增加。
资助
提契诺心脏中心研究所，瑞士卢加诺州立医院。
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