Role of Complement Activation in Severe COVID-19

补体激活在严重 COVID-19 中的作用

• 批准号: 10687821
• 负责人: Xuebin Qin
• 金额: $ 67.43万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 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/10687821
• 关键词: 2019-nCoV; Acceleration; 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 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; Macrophage; Mannose Binding Lectin; Mediating; Modeling; Monoclonal Antibodies; Mus; Myeloid Cell Activation; Myeloid Cells; Organ; Pathogenesis; Pathologic; Pathway interactions; Platelet Activation; Predisposition; Rationalization; Research; Risk; Role; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; SARS-CoV-2 variant; Safety; Site; System; Testing; Therapeutic; Thrombosis; Transgenic Mice; Vascular Diseases; Vascular Permeabilities; activation product; cell injury; clinically relevant; complement system; immune activation; inhibitor; interest; interstitial; membrane assembly; mortality; novel therapeutic intervention; overexpression; response; secondary infection; severe COVID-19; single-cell RNA sequencing; therapeutic evaluation; tool; vascular inflammation

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.

项目摘要/摘要：响应特别关注通知（NOSI）：补充基本 免疫学（CIBI），我们建议检查补体在严重的 2019冠状病毒病。补体系统通过三种途径之一激活-经典的，替代的， 甘露糖结合凝集素（MBL）-在C3裂解时会聚，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是一种细胞溶解剂， 在病理条件下可插入宿主细胞膜的大分子孔。广泛 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， 多器官损伤导致严重的COVID-19。然而，C和MAC的致病作用在严重 COVID-19尚未进行实验研究。拟议的研究将利用我们新开发的 阻断或修饰C激活产物以研究C在内皮细胞中的作用的最新工具 严重COVID-19中观察到的损伤、血小板活化和血栓形成，包括治疗性 范例为了满足我们的需求，我们建立了一种严重COVID的动物模型并进行了表征- 19使用SARS-CoV-2感染的K18-hACE 2小鼠。小鼠出现急性呼吸窘迫综合征 （ARDS）、进行性体重减轻和7天时的死亡率，其与严重间质性炎症相关， 血管周围炎症、血小板活化和肺部血栓形成。我们还观察到（i）内皮细胞 (EC)肺泡隔功能障碍;（ii）与广泛的 免疫细胞的活化（例如，肺巨噬细胞）;和（iii）增加C3和MAC沉积， 肺血管此外，单细胞RNAseq显示，在这种情况下， 严重的COVID-19模型。这些结果促使我们假设，C在一般情况下，和MAC在 特别是，显著促进EC损伤、血小板活化和血栓形成， COVID-19的严重病例。目的1将研究抑制C激活和MAC形成是否会 减少SARS-CoV-2感染K18小鼠的EC损伤和血小板和凝血途径活化。目的2 将测试MAC形成的限制将防止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。 目的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。帮助我们更好地理解C激活的作用 和MAC在重症COVID-19发病机制中的作用，为COVID-19的预防和治疗开辟了新的途径， 涉及C系统调节的新治疗策略的开发。