Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans

阐明遗传性​​补体系统缺陷在败血症和暴发性紫癜分子病理生理学中的作用

• 批准号: 10246412
• 负责人: Pavan Bendapudi
• 金额: $ 13.13万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246412
• 关键词: Address; Age; Anti-Inflammatory Agents; Anticoagulation; Bacterial Infections; Biological; Biological Markers; Blood Coagulation Disorders; Cells; Cessation of life; Clinical; Coagulation Process; Code; Complement; Complement component C1; Complication; Data; Data Set; Defect; Development; Disease; Disseminated Intravascular Coagulation; Ethnic Origin; Factor Xa; Failure; Foundations; Functional disorder; Generations; Genetic; Genetic Predisposition to Disease; Goals; Human; Individual; Infection; Inflammation; Inflammatory; Inherited; Integrins; Intervention; Lead; Link; Macrophage-1 Antigen; Molecular; Molecular Profiling; Mutation; National Heart, Lung, and Blood Institute; Natural Immunity; Neisseria meningitidis; Organ; Pathway interactions; Patients; Pattern; Plasma; Play; Population; Production; Proteins; Public Health; Purpura Fulminans; Research; Role; Sepsis; Signal Pathway; Signal Transduction; Specimen; Streptococcus pneumoniae; Therapeutic Intervention; Thromboplastin; Thrombosis; U937 Cells; Up-Regulation; Variant; Work; biobank; clinical predictors; cohort; comorbidity; comorbidity Index; complement pathway; complement system; cytokine; disease phenotype; exome sequencing; follow-up; gain of function; gene discovery; immunoregulation; insight; loss of function; macrophage; monocyte; mortality; mutant; mutational status; novel; pathogen exposure; pathogenic microbe; receptor; repository; response; septic; septic patients; sex; systemic inflammatory response; thromboinflammation; thrombotic; trend

PROJECT SUMMARY Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients develop a highly thrombotic subtype of disseminated intravascular coagulation (DIC), leading to dismemberment, end organ damage, and death. PF can be triggered by a range of bacterial infections and is distinguished by extremely high levels of circulating cytokines and failure of key anti-inflammatory pathways which cause a marked upregulation of procoagulant tissue factor (TF) expression by activated monocytes. Because PF represents an extreme disease phenotype, leveraging our findings in this disorder could yield key insights into the broader problem of septic DIC. However, at present almost nothing is known about the molecular pathophysiology and genetic predisposition underlying PF. Utilizing germline whole exome sequencing (WES) and a targeted gene discovery approach, we have found a significant enrichment in rare, deleterious coding variants in the complement systems of patients with PF compared to unselected patients with sepsis (P<0.0001). Intriguingly, we also found that these variants may be associated with increased mortality in unselected sepsis patients despite the absence of overt PF. We hypothesize that complement system defects lead to heightened systemic inflammation and procoagulant activity, resulting in the development of coagulopathy. In Aim 1 of this project, we will follow up on our preliminary results by performing WES on clinically well-annotated specimens in the NHLBI BioLINCC repository from septic patients without overt PF. We will correlate complement mutational status to plasma biomarkers of thrombosis and inflammation after adjusting for age, sex, ethnicity, and comorbidities in order to understand if complement system defects are associated with worsened thrombo-inflammation in sepsis. In Aim 2, we will functionally characterize a novel class of rare PF-associated variants in complement receptors 3 and 4 (CR3/4) with respect to their impact on monocyte-driven inflammation and thrombosis. The proposed work will provide important new insights into the relationship between innate immunity and dysregulated coagulation and generate a foundational WES dataset with biological correlates for studying the widespread problem of coagulopathy in sepsis.

项目概要 暴发性紫癜（PF）是脓毒症的一种罕见但具有破坏性的并发症，患者 发展出弥散性血管内凝血（DIC）的高度血栓亚型，导致 肢解、终末器官损伤和死亡。 PF 可由多种细菌引发 感染，其特征是循环细胞因子水平极高和关键细胞因子衰竭 导致促凝血组织因子显着上调的抗炎途径 (TF) 被激活的单核细胞表达。因为 PF 代表一种极端的疾病表型， 利用我们在这种疾病中的发现可以为更广泛的脓毒症问题提供重要见解 DIC。然而，目前人们对分子病理生理学和免疫学几乎一无所知。 PF 的遗传易感性。利用种系全外显子组测序 (WES) 和 通过靶向基因发现方法，我们发现稀有、有害的基因显着富集 与未选择的患者相比，PF 患者补体系统中的编码变异 脓毒症（P<0.0001）。有趣的是，我们还发现这些变异可能与 尽管没有明显的 PF，但未经选择的脓毒症患者的死亡率仍增加。我们 假设补体系统缺陷导致全身炎症加剧 促凝血活性，导致凝血病的发生。在这个项目的目标 1 中，我们 将通过对临床充分注释的 WES 来跟进我们的初步结果 NHLBI BioLINCC 存储库中来自没有明显 PF 的脓毒症患者的标本。我们将 将补体突变状态与血栓和炎症的血浆生物标志物相关联 在调整年龄、性别、种族和合并症后，以了解补体是否 系统缺陷与脓毒症中血栓炎症恶化有关。在目标 2 中，我们将 对补体受体中一类罕见的 PF 相关变异进行功能表征 3 和 4 (CR3/4) 关于它们对单核细胞驱动的炎症和血栓形成的影响。 拟议的工作将为先天之间的关系提供重要的新见解 免疫和凝血失调，并生成基础 WES 数据集 研究脓毒症中普遍存在的凝血病问题的生物学相关性。