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

纤溶酶原/纤维蛋白原轴与 COVID-19 发病机制的联系机制

• 批准号: 10471424
• 负责人: MATTHEW J FLICK
• 金额: $ 55.17万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471424
• 关键词: 2019-nCoV; ACE2; Acute Respiratory Distress Syndrome; Alveolar; Automobile Driving; Autopsy; Blood; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Vessels; Blood coagulation; C-reactive protein; COVID-19; COVID-19 morbidity; COVID-19 mortality; COVID-19 pandemic; COVID-19 pathogenesis; COVID-19 patient; COVID-19 treatment; Capsid Proteins; Cell surface; Cessation of life; Clinical; Clinical Management; Coagulation Process; Coronavirus; Coronavirus Infections; Coupling; Data; Deposition; Disease; Engineering; Fibrin; Fibrin fragment D; Fibrinogen; Fibrosis; Fostering; Functional disorder; Goals; Healthcare Systems; Hematology; Hemorrhage; Hemostatic Agents; Human; Hypoxia; Immune response; Immunologics; Individual; Infection; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-6; Knowledge; Lead; Leukocytes; Link; Lung; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Organ; Organ failure; Outcome; Pathogenicity; Pathology; Patient-Focused Outcomes; Patients; Persons; Plasminogen; Public Health; Pulmonary Edema; Pulmonary Inflammation; Reporting; Research; Structure of parenchyma of lung; Surface; Symptoms; System; Testing; Thrombophilia; Thrombosis; Tissues; Translations; Viral Proteins; Virus; body system; coronavirus disease; coronavirus receptor; cost; cytokine release syndrome; experience; human coronavirus; improved; inflammatory marker; insight; mortality; novel; patient response; programs; severe COVID-19; systemic inflammatory response; tool; trigger point

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.

概括 严重的急性呼吸综合征冠状病毒2（SARS-COV-2; COV2）是第一个高度致病性的 高度可传播的人冠状病毒是世界范围内大流行的致病药物。作为 在2020年11月，据报道，全世界有5000万例COV2感染和125万例死亡。 美国大部分案件的占970万（20％）和死亡235,000（19％），而Covid-19是 预计将为美国医疗保健系统增加8万亿美元的伯宁。一个特别挑战的方面 临床管理是患者对COV2感染的可变反应。一些感染者报告很​​少 症状，而其他症状则表现为低氧特征，急性呼吸窘迫 综合征和可能导致死亡的多器官参与。 COVID的促炎性“细胞因子风暴” 19例患者促进了血管功能和血液组成的进化。纤维蛋白原和D-升高 二聚体（纤维蛋白布的分解产物）轨道具有显着升高的炎症标记（例如IL-6， C反应蛋白），它与差的患者预后显着和正相关。尸检研究 COVID-19患者显示在肺组织和其他器官中血管内和血管外纤维蛋白沉积物 系统。当前的关键知识差距是持续性纤维蛋白沉积如何发展和 它们是否在功能上与严重Covid-19疾病的病理生理有关。我们的中心 假设纤溶酶原激活（PA）系统的不足是过渡的触发点 由于积累，促炎和组织纤维蛋白的累积，促疾病和组织的纤维蛋白 肺部和其他器官系统中的沉积物。为了检验这一假设，我们的研究团队开发了 小鼠适应的COV2病毒复制了Covid-19的关键免疫学和血液学方面 人类。该独特的工具将与携带单个或组合缺陷或组合的小鼠一起使用 纤维蛋白原或PA系统组件中的功能突变，以定义止血的自然过程 感染后的变化并阐明了凝血和纤维蛋白水解因子对 主机响应。特别是，我们将确定（i）宿主因素的局部和系统活动的差异 在轻度与严重的COV2感染后，控制纤维蛋白（OGEN）沉积，稳定和溶解； （ii） PA缺乏症如何促进COV2感染后的严重疾病，其特征是局部恶化 以及系统性炎症，器官损伤和宿主死亡率； （iii）将纤维蛋白（ogen）连接到的机制 COV2感染后，宿主炎症反应加剧和严重疾病的诱导。这 拟议的研究将提供有关纤溶酶原/纤维蛋白原轴对纤维蛋白原/纤维蛋白原轴的贡献的新见解。 COV2病理生物学，阐明PA系统组件中的关键机制耦合到COV2- 介导的血小板，组织损伤和器官功能丧失，并提供必要的原则证明 数据以促进发现结果转化为Covid-19的新疗法。