Endothelial Cell and Cardiomyocyte Dysfunction in Children with Kawasaki disease-like SARS-CoV-2 Induced Immune Activation

类川崎病 SARS-CoV-2 诱导的免疫激活儿童的内皮细胞和心肌细胞功能障碍

• 批准号: 10165329
• 负责人: JANE C BURNS
• 金额: $ 72.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165329
• 关键词: 2019-nCoV; Acute; Address; Administrative Supplement; Affect; Age; Aneurysm; Antibodies; Area; Biological Assay; Biological Markers; Blood; COVID-19 pandemic; Cardiac Myocytes; Cardiovascular system; Cells; Child; Childhood; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Coronary artery; Data; Diagnosis; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Etiology; Exposure to; Fever; Functional disorder; Funding; Goals; Heart Diseases; Heart failure; Immune; In Vitro; Incubated; Infection; Inflammasome; Inflammation; Inflammatory; Intensive Care Units; Interleukin-1; Interleukin-6; Intravenous Immunoglobulins; Laboratories; Lung diseases; Mediating; Modeling; Molecular; Molecular Profiling; Mucocutaneous Lymph Node Syndrome; Outcome; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Plasma; Publications; RNA; Reaction; Reporting; Research; Resistance; Sampling; Serum; Shock; Site; Steroids; Syndrome; TNF gene; Therapeutic; Time; Tube; Vasculitis; Virus; Western Blotting; Western Europe; Whole Blood; Work; anakinra; cardiovascular health; comparative effectiveness trial; cytokine; drug efficacy; efficacy testing; immune activation; inflammatory marker; neutrophil; patient population; pediatric patients; response; transcriptome sequencing; treatment guidelines

Project Summary In the wake of COVID-19 pandemic, fever with severe systemic inflammation and shock, known as Pediatric Inflammatory Multisystem Syndrome (PIMS), has evolved as a new threat to children. PIMS was originally reported in Western Europe and the number of cases is rapidly increasing in the U.S. A hallmark of PIMS has been heart failure leading to shock and the absence of significant pulmonary disease. The clinical presentation in these patients shares many features with Kawasaki disease (KD), the most common cause of acquired heart disease in children, which itself can present with distributive shock requiring inotropic and vasoactive support in the intensive care unit. Several PIMS patients are either SARS-CoV-2 PCR positive or have developed antibodies against SARS-CoV-2, suggesting that PIMS is an immune-mediated reaction to antecedent exposure to the virus. Curiously, at the same time that patients are being diagnosed with PIMS, the numbers of children with typical KD has increased dramatically in these same regions. The emergence of PIMS is so new and so rapidly evolving that there are literally no publications, treatment guidelines or clinical trials related to these seriously affected pediatric patients. Through our network of 30 pediatric centers participating in KIDCARE, our comparative effectiveness trial for treatment-resistant KD funded by PCORI, we are collecting patient data and clinical samples to support the work proposed here. The goal of this administrative supplement is to analyze demographic, clinical and laboratory data in conjunction with assays using patient cells and sera, which will allow us to study the relationships among SARS-CoV-2 infection, typical KD, and PIMS and to model different therapeutic strategies against PIMS. Three specific aims are proposed to achieve this goal. Specific Aim 1 will profile and compare clinical features of PIMS and typical KD. Demographic and clinical data and the neutrophil response to intravenous immunoglobulin (IVIG) will be compared between these two illnesses. Cytokine profiles and inflammatory markers in plasma from acute and subacute PIMS and typical KD will also be compared. Specific Aim 2 will elucidate molecular features of PIMS and compare with typical KD. We will use RNA-seq, ELISA, and Western blot analyses to profile changes in levels of molecules related to inflammation (e.g., TIFA, NFkβ, NLRP3-inflammasome, IL-1, IL-6, TNFα) and cardiovascular health (KLF4, miR-483, ACE2) in endothelial cells and cardiomyocytes. Specific Aim 3 will test the efficacy of drug therapy for PIMS by comparing the in vitro effects of intravenous immunoglobulin, steroids, and anakinra on inflammatory pathways and cardiovascular biomarkers in endothelial cells and cardiomyocytes treated with sera from acute PIMS patients prior to therapy. The synergistic expertise of the investigative teams in this multi-PI supplement provides a unique opportunity to understand the clinical features, molecular basis, and efficacy of drug treatment of PIMS as compared to KD.

项目概要 在 COVID-19 大流行之后，发烧并伴有严重的全身炎症和休克，称为小儿科 炎症性多系统综合症（PIMS）最初是对儿童的一种新威胁。 西欧有报道，美国的病例数量正在迅速增加。PIMS 的一个特点是 心力衰竭导致休克且没有明显的肺部疾病。 这些患者与川崎病 (KD) 具有许多共同特征，川崎病是获得性心脏病的最常见原因 儿童疾病，其本身可表现为分布性休克，需要正性肌力和血管活性支持 重症监护病房中的几名 PIMS 患者要么 SARS-CoV-2 PCR 呈阳性，要么已经出现感​​染。 针对 SARS-CoV-2 的抗体，表明 PIMS 是对先前暴露的免疫介导反应 奇怪的是，在患者被诊断出患有 PIMS 的同时，儿童的数量也在增加。 典型的 KD 在这些相同的地区急剧增加 PIMS 的出现是如此新奇。 迅速发展，实际上没有与这些相关的出版物、治疗指南或临床试验 通过我们参与 KIDCARE 的 30 个儿科中心网络，我们的儿科患者受到了严重影响。 由 PCORI 资助的难治性 KD 比较有效性试验，我们正在收集患者数据并 支持此处提出的工作的临床样本 本行政补充的目标是进行分析。 人口统计、临床和实验室数据以及使用患者细胞和血清进行的检测， 将使我们能够研究 SARS-CoV-2 感染、典型 KD 和 PIMS 之间的关系，并建立模型 针对 PIMS 的不同治疗策略提出了三个具体目标。 目标 1 将分析和比较 PIMS 的临床特征和典型的 KD 的人口统计和临床数据。 将比较这两种疾病之间的中性粒细胞对静脉注射免疫球蛋白 (IVIG) 的反应。 急性和亚急性 PIMS 以及典型 KD 血浆中的细胞因子谱和炎症标志物也将 具体目标 2 将阐明 PIMS 的分子特征，并与典型的 KD 进行比较。 使用 RNA-seq、ELISA 和蛋白质印迹分析来分析与炎症相关的分子水平的变化 （例如 TIFA、NFkβ、NLRP3 炎症小体、IL-1、IL-6、TNFα）和心血管健康（KLF4、miR-483、ACE2） 具体目标 3 将通过内皮细胞和心肌细胞测试 PIMS 药物治疗的功效。 比较静脉注射免疫球蛋白、类固醇和阿那白滞素对炎症途径的体外影响 用急性 PIMS 血清处理的内皮细胞和心肌细胞中的心血管生物标志物 研究团队在这种多 PI 补充剂中的协同专业知识提供了治疗前的患者。 了解 PIMS 的临床特征、分子基础和药物治疗功效的独特机会 与KD相比。