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：回应特殊兴趣通知（NOSI）：基本补充 免疫学（CIBI），我们建议检查完成对严重发病机理的病原体作用 新冠肺炎。完成系统是通过三种途径之一激活的（替代，替代方案和 Mannose结合讲座（MBL） - 在C3裂解时收敛，导致C3和C5的形成 转换酶并以膜攻击复合物（MAC）的组装结束。 MAC是一种细胞溶解 大分子孔可以在病理条件下插入宿主细胞膜中。广泛的 从他人那里获得的证据表明，完成（c）系统，尤其是Mac，可能 参与介导的内皮损伤，激活凝结途径和血小板，并引起 多器官损伤导致严重的covid-19。但是，C和MAC在严重 Covid-19尚未经过实验研究。拟议的研究将利用我们新开发的 阻止或修改C激活产物以研究C在内皮细胞中的作用的最先进工具 损害，血小板激活和在严重的共同-19中看到的损伤，血栓形成，包括治疗 范式。为了满足我们的需求，我们已经建立并表征了一个严重互联的动物模型 19使用SARS-COV-2感染的K18-HACE2小鼠。小鼠患急性呼吸窘迫综合征 （ARDS），与严重间质性炎症有关的7天的渐进式体重减轻和死亡率， 血管周围注射，血小板激活和肺部血栓形成。我们还观察（i）内皮细胞 （EC）肺泡隔隔的功能障碍； （ii）与广泛相关的血管通透性增加 免疫细胞的激活（例如肺巨噬细胞）； （iii）增加C3和MAC沉积 肺脉管系统。此外，单细胞RNASEQ显示了肺中的C激活和凝结 严重的Covid-19模型。这些结果促使我们假设C一般C，而Mac在 特别，显着促进EC损伤，血小板激活和血栓形成 严重的covid案例。 AIM 1将研究C激活和MAC形成的抑制是否会 在SARS-COV-2感染的K18小鼠中减少EC损伤，血小板和凝结途径激活。目标2 将检验以下假设：MAC形成的限制将防止EC损害和激活 髓样细胞，导致SARS-COV-2感染的K18小鼠的血小板减少和凝血活化。 AIM 3将研究C在SAR-COV-2感染的发病机理中的作用 评估靶向位点的C抑制作用作为COVID-19的治疗方法。帮助我们更好地了解C激活的作用 MAC在严重的Covid-19的发病机理中，开放了一种新的预防和治疗Covid-19的途径，并寄养 新的治疗策略的发展涉及对C系统的调节。