Role of Complement Activation in Severe COVID-19

补体激活在严重 COVID-19 中的作用

基本信息

批准号：
10512248
负责人：
Xuebin Qin
金额：
$ 69.08万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-20 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512248
关键词：
2019-nCoV Acute Respiratory Distress Syndrome Address Alveolar Aneurysm Animal Model Atherosclerosis Attenuated Biological Availability Blood Platelets Body Weight decreased COVID-19 COVID-19 prevention COVID-19 severity COVID-19 treatment Cell membrane Cells Clinical Trials Coagulation Process Communicable Diseases Complement Complement 3 Convertase Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Deposition Development Endothelial Cells Endothelium Erythrocytes Fostering Functional disorder Hemolysis Human Immunology Infection Inflammation Investigation K-18 conjugate Knock-in Knock-out Lung Mannose Binding Lectin Mediating Modeling Monoclonal Antibodies Mus Myeloid Cell Activation Myeloid Cells Organ Pathogenesis Pathologic Pathway interactions Platelet Activation Predisposition Research Risk Role SARS-CoV-2 infection SARS-CoV-2 pathogenesis SARS-CoV-2 variant Safety Site System Testing Therapeutic Thrombosis Transgenic Mice Transgenic Organisms Vascular Diseases Vascular Permeabilities activation product cell injury clinically relevant complement pathway complement system immune activation inhibitor interest interstitial macrophage membrane assembly mortality novel therapeutic intervention overexpression response secondary infection severe COVID-19 single-cell RNA sequencing therapeutic evaluation tool

项目摘要

Project summary/Abstract: In response to Notice of Special Interest (NOSI): Complement in Basic Immunology (CIBI), we propose to examine the causative effect of complements in the pathogenesis of severe COVID-19. The complement system is activated via one of three pathways—classical, alternative, and mannose-binding lectin (MBL)—which converge at C3 cleavage, leading to the formation of C3 and C5 convertases and concluding with assembly of the membrane attack complex (MAC). MAC is a cytolytic macromolecular pore that can insert into host cell membranes under pathological conditions. Extensive evidence obtained from others and us indicates that the complement (C) system, in particular MAC, may participate in mediating endothelial damage, activating the coagulation pathway and platelets, and causing multiple organ damage leading to severe COVID-19. However, the causative roles of C and MAC in severe COVID-19 have not been experimentally investigated. The proposed studies will utilize our newly developed state-of-the-art tools to block or modify the C activation products to investigate the role of C in endothelial cell damage, platelet activation, and thrombosis formation seen in severe COVID-19, including therapeutic paradigms. To address our needs, we have established and characterized an animal model of severe COVID- 19 using SARS-CoV-2-infected K18-hACE2 mice. The mice develop acute respiratory distress syndrome (ARDS), progressive weight loss, and mortality at 7 days that is associated with severe interstitial inflammation, perivascular inflammation, platelet activation, and thrombosis in the lungs. We also observe (i) endothelial cell (EC) dysfunction of the alveolar septa; (ii) increased vascular permeability associated with the extensive activation of immune cells (e.g., lung macrophage cells); and (iii) increased C3 and MAC deposition in pulmonary vasculature. In addition, single-cell RNAseq shows C activation and coagulation in the lungs of this severe COVID-19 model. These results have prompted us to hypothesize that the C in general, and MAC in particular, significantly contribute to the EC damage, platelet activation, and thrombosis formation seen in severe cases of COVID-19. Aim 1 will investigate whether the inhibition of C activation and MAC formation will reduce EC damage and platelet and coagulation pathway activation in SARS-CoV-2-infected K18 mice. Aim 2 will test the hypothesis that the restriction of MAC formation will protect against EC damage and activation of the myeloid cells, leading to reduced platelet and coagulation activation in SARS-CoV-2-infected K18 mice. Aim 3 will investigate the role of C in the pathogenesis of SAR-CoV-2 infection in a clinically relevant paradigm and evaluate site-targeted C inhibition as a treatment for COVID-19. help us better understand the role of C activation and the MAC in pathogenesis of severe COVID-19, open a new avenue to prevent and treat COVID-19, and foster the development of new therapeutic strategies involving modulation of the C system.

项目概要/摘要：响应特别兴趣通知（NOSI）：基础补充免疫学（CIBI），我们建议检查补体在严重疾病发病机制中的致病作用 COVID-19 补体系统通过三种途径之一激活：经典途径、替代途径和甘露糖结合凝集素 (MBL) — 在 C3 裂解处汇聚，导致 C3 和 C5 的形成转化酶并以膜攻击复合物 (MAC) 的组装结束，MAC 是一种溶细胞物质。在病理条件下可以广泛插入宿主细胞膜的大分子孔。从其他人和我们获得的证据表明，补体 (C) 系统，特别是 MAC，可能参与介导内皮损伤，激活凝血途径和血小板，引起多器官损伤导致严重的 COVID-19 然而，C 和 MAC 在重症中的致病作用。 COVID-19 尚未经过实验研究。拟议的研究将利用我们新开发的。最先进的工具来阻断或修饰 C 激活产物，以研究 C 在内皮细胞中的作用严重 COVID-19 中出现的损伤、血小板活化和血栓形成，包括治疗为了满足我们的需求，我们建立了严重新冠病毒动物模型并对其进行了表征。 19 使用感染 SARS-CoV-2 的 K18-hACE2 小鼠进行实验，这些小鼠出现急性呼吸窘迫综合征。 (ARDS)、进行性体重减轻以及与严重间质炎症相关的 7 天死亡率，我们还观察到（i）内皮细胞的血管周围炎症、血小板活化和血栓形成。 (EC) 肺泡间隔功能障碍；(ii) 与广泛的血管通透性相关的增加免疫细胞（例如肺巨噬细胞）的激活；以及 (iii) C3 和 MAC 沉积增加；此外，单细胞 RNAseq 显示该肺中存在 C 激活和凝血。这些结果促使我们对一般的 C 和 MAC 进行混淆。特别是，显着促进 EC 损伤、血小板活化和血栓形成目标 1 将研究 C 激活和 MAC 形成的抑制是否会影响 COVID-19 的严重病例。减少 SARS-CoV-2 感染的 K18 小鼠的 EC 损伤以及血小板和凝血途径激活。将检验限制 MAC 形成将防止 EC 损伤和激活的假设骨髓细胞，导致 SARS-CoV-2 感染的 K18 小鼠血小板和凝血激活减少。目标 3 将在临床相关范例中研究 C 在 SAR-CoV-2 感染发病机制中的作用，评估位点靶向 C 抑制作为 COVID-19 的治疗方法有助于我们更好地了解 C 激活的作用。和 MAC 在严重 COVID-19 发病机制中的作用，开辟预防和治疗 COVID-19 的新途径，并促进涉及 C 系统调节的新治疗策略的开发。