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

总结 严重急性呼吸综合征冠状病毒2型（SARS-CoV-2; CoV 2）是第一种高致病性， 高度传播的人类冠状病毒，是全球COVID-19大流行的病原体。作为 截至2020年11月，全球已报告5000万例CoV 2感染病例和125万例死亡。 美国占大多数病例，970万（20%）和死亡235，000（19%），COVID-19是 预计将为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CoV 2感染的可变反应。一些感染者报告很少 而其他人则表现出严重的疾病，其特征是缺氧、急性呼吸窘迫 综合征和多器官受累，可能导致死亡。COVID中的促炎性“细胞因子风暴”- 19例患者促进血管功能和血液成分紊乱。纤维蛋白原和D- 二聚体（纤维蛋白凝块的分解产物）跟踪炎性标记物的显著升高（例如，IL-6， C-反应蛋白），这与不良患者结局显著正相关。尸体解剖研究 COVID-19患者在肺组织和其他器官中发现血管内和血管外纤维蛋白沉积 系统.目前关键的知识缺口是持续性纤维蛋白沉积如何发展的分子基础， 它们是否在功能上与严重COVID-19疾病的病理生理学相关。我们的中央 假设纤溶酶原激活（PA）系统的不足是纤溶酶原激活（PA）系统转变的触发点， COVID-19从轻度到重度疾病由于积累，促炎和组织损伤纤维蛋白 沉积在肺和其他器官系统中。为了验证这一假设，我们的研究团队开发了一个 小鼠适应的CoV 2病毒，复制COVID-19的关键免疫学和血液学方面， 人类这种独特的工具将与携带单一或组合缺陷的小鼠一起使用， 纤维蛋白原或PA系统组分的功能突变，以确定止血的自然过程 感染后的变化，并阐明凝血和纤溶因子的功能贡献， 主机响应。具体而言，我们将确定（i）宿主因子的局部和全身活性的差异 控制纤维蛋白（原）沉积、稳定化和溶解的轻度与重度CoV 2感染;（ii） PA缺乏如何促进CoV 2感染后以局部恶化为特征的严重疾病 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 宿主炎症反应的恶化和CoV 2感染后严重疾病的诱导。的 拟议的研究将提供新的见解纤溶酶原/纤维蛋白原轴的贡献， CoV 2病理生物学，阐明PA系统组件与CoV 2耦合缺陷的关键机制- 介导的血栓形成倾向、组织损伤和器官功能丧失，并提供必要的原理证明 数据，以促进将发现转化为新的COVID-19治疗方法。

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.