Mechanisms linking the plasminogen/fibrinogen axis to the pathogenesis of COVID-19

摘要 严重急性呼吸综合征冠状病毒-2(SARS-CoV-2；CoV2)是第一种高致病性和 高度传染性的人类冠状病毒，是全球新冠肺炎大流行的病原体。AS 截至2020年11月，全球报告了5000万例CoV2感染病例和125万例死亡。 美国占大多数，970万例(20%)，死亡23.5万例(19%)，新冠肺炎是 预计将给美国医疗保健系统增加8万亿美元的负担。一个特别具有挑战性的方面 临床管理是患者对CoV2感染的不同反应。一些感染者报告很少 其他症状表现为严重疾病，特征为缺氧、急性呼吸窘迫 综合症，以及可导致死亡的多器官受累。COVID中的一场促炎“细胞因子风暴”- 19名患者促进了血管功能和血液成分的紊乱。纤维蛋白原和D- 二聚体(纤维蛋白凝块的分解产物)跟踪炎症标志物(例如，IL-6， C-反应蛋白)，与不良的患者预后显著正相关。身体解剖研究 新冠肺炎患者发现肺组织和其他器官有血管内和血管外纤维蛋白沉积 系统。目前一个关键的知识缺口是持续性纤维蛋白沉积如何发展和发展的分子基础 它们是否在功能上与严重新冠肺炎病的病理生理有关。我们的中央 假设纤溶酶原激活(PA)系统的不足是 新冠肺炎从轻度到重度疾病，由纤维蛋白积聚、促炎和组织破坏引起 肺和其他器官系统内的沉积物。为了验证这一假设，我们的研究团队开发了一种 复制新冠肺炎主要免疫学和血液学方面的小鼠适应的CoV2病毒 人类。这一独特的工具将与携带单一或联合缺陷或 纤维蛋白原或PA系统成分的功能突变定义止血的自然过程 感染后的变化并阐明凝血和纤溶因子对 主机响应。具体地说，我们将确定(I)宿主因素的局部和系统活动的差异 控制轻微和重度CoV2感染后纤维蛋白(原)的沉积、稳定和溶解；(Ii) PA缺乏如何促进以局部加重为特征的CoV2感染后的严重疾病 和全身炎症、器官损伤和宿主死亡率；以及(Iii)将纤维蛋白(原)与 CoV2感染后宿主炎症反应的加剧和严重疾病的诱导。这个 拟议的研究将为纤溶酶原/纤维蛋白原轴对 CoV2病理生物学，阐明PA系统组件中的缺陷与CoV2耦合的关键机制- 调节血栓形成、组织损伤和器官功能丧失，并提供必要的原则证明 为将研究结果转化为新冠肺炎新疗法提供便利的数据。

SUMMARY Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2; CoV2) is the first highly pathogenic and highly transmissible human coronavirus that is the causative agent for the worldwide COVID-19 pandemic. As of November 2020, 50 million cases of CoV2 infection worldwide and 1.25 million deaths have been reported. The U.S. accounts for the majority of cases, 9.7 million (20%) and deaths 235,000 (19%), and COVID-19 is expected to add an $8 trillion burden to the U.S. health care system. A particularly challenging aspect of clinical management is the variable patient response to CoV2 infection. Some infected individuals report few symptoms whereas others display severe disease characterized by hypoxia, acute respiratory distress syndrome, and multi-organ involvement that can lead to death. A pro-inflammatory ‘cytokine storm’ in COVID- 19 patients promotes derangements in vascular function and blood composition. Elevated fibrinogen and D- dimer (the breakdown product of fibrin clots) track with significant elevations inflammatory markers (e.g., IL-6, C-reactive protein), which significantly and positively correlate with poor patient outcomes. Autopsy studies of COVID-19 patients have revealed intravascular and extravascular fibrin deposits in lung tissue and other organ systems. A current critical knowledge gap is the molecular basis of how persistent fibrin deposits develop and whether they are functionally linked to the pathophysiology of severe COVID-19 disease. Our central hypothesis that an insufficiency in the plasminogen activation (PA) system is a trigger point for transition of COVID-19 from mild to severe disease due accumulating, proinflammatory, and tissue-damaging fibrin deposits within the lung and other organ systems. To test this hypothesis, our research team developed a mouse-adapted CoV2 virus that replicates key immunological and hematological aspects of COVID-19 in humans. This unique tool will be used in conjunction with mice carrying single or combined deficiencies or functional mutations in fibrinogen or PA system components to define the natural course of hemostatic changes following infection and elucidate functional contributions of coagulation and fibrinolytic factors to the host response. Specifically, we will determine (i) the differences in local and systemic activity of host factors that control fibrin(ogen) deposition, stabilization, and dissolution following mild vs. severe CoV2 infection; (ii) how PA deficiency promotes severe disease following CoV2 infection characterized by exacerbation of local and systemic inflammatory, organ damage, and host mortality; and (iii) the mechanisms linking fibrin(ogen) to exacerbation of host inflammatory responses and induction of severe disease following CoV2 infection. The proposed studies will provide novel insights into the contribution of the plasminogen/fibrinogen axis to the CoV2 pathobiology, illuminate key mechanisms coupling deficiencies in PA system components to CoV2- mediated thrombophilia, tissue damage, and loss of organ function, and provide essential proof-of-principle data to facilitate translation of findings into new treatments for COVID-19.