Mechanisms of childhood obesity underlying the susceptibility to multisystem inflammatory syndrome in children (MIS-C)

儿童肥胖导致儿童多系统炎症综合征易感性的机制（MIS-C）

• 批准号: 10450145
• 负责人: Janet Chou
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450145
• 关键词: 12 year old; 2019-nCoV; Accounting; Acute; Adult; Autoimmune Diseases; Biological; Biological Markers; Blood Coagulation Disorders; Body mass index; Body measure procedure; COVID-19; COVID-19 detection; COVID-19 test; COVID-19 vaccine; Cells; Child; Childhood; Clinic; Collaborations; Communities; Complication; Coronary Aneurysm; Data; Data Analyses; Data Set; Development; Disease; Education; Endocrinology; Equilibrium; Europe; Exanthema; Exhibits; Fever; Functional disorder; Genetic Polymorphism; Genetic Risk; Genetic Screening; Genetic study; Goals; Hematological Disease; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Lymphopenia; Mediating; Metabolism; Multiomic Data; Multisystem Inflammatory Syndrome in Children; Myocardial dysfunction; Obesity; Only Child; Overweight; Patients; Phase; Population; Predisposition; Prevalence; Public Health; Pulmonary Heart Disease; Research Personnel; Risk; Risk Assessment; Risk Factors; SARS-CoV-2 infection; Sampling; Severities; Shock; Signal Transduction; Symptoms; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; United States; Vaccine Clinical Trial; Variant; Viral; Virus; Virus Diseases; Weight; acute infection; cohort; comorbidity; cytopenia; disorder risk; gastrointestinal symptom; genetic risk factor; genetic variant; immune activation; insight; multiple omics; obesity genetics; obesity in children; overweight child; post SARS-CoV-2 infection; severe COVID-19

PROJECT SUMMARY/ABSTRACT Unpredictability is the hallmark of Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a severe pediatric complication of SARS-CoV-2 infection. MIS-C is distinct from COVID-19. It is not associated with pre-existing cardiopulmonary, autoimmune, or hematologic disorders. It can occur either during acute phase with detectable SARS-CoV-2 virus, or in the post-infectious period of several weeks after acute infection. Milder symptoms of MIS-C include fevers, rashes, and gastrointestinal symptoms, but can progress to cytopenias, coagulopathy, myocardial dysfunction, coronary aneurysms, and/or shock. We and others have found that MIS- C is associated with pediatric overweight and obesity, thereby identifying over 380 million children at risk for this disease. The mechanisms by which overweight and obesity influence the development of MIS-C are unknown. Until a vaccine against SARS-CoV-2 is globally available to all children, they will remain vulnerable to MIS-C. Our preliminary studies indicate that MIS-C is a highly inflammatory disease that incites more severe immune cell activation than COVID-19, particularly in overweight and obese children. Overweight and obese children with MIS-C had more T cell lymphopenia and T cell activation than their normal weight counterparts, suggesting an increased risk for more severe disease. Deleterious genetic variants increasing IFN and inflammatory signaling were exclusively found in patients with MIS-C, rather than severe COVID-19. This is a mechanistic counterpoint to defective IFN signaling associated with severe COVID-19 in adults. Our central hypothesis is that pediatric overweight and obesity prime interferon signaling, thereby increasing T cell activation and ultimately, the risk of MIS-C Aim 1 will elucidate how pediatric overweight and obesity drive immune cell dysfunction during MIS-C. The proposed studies will test the hypotheses that pediatric overweight and obesity are associated with more severe MIS-C, characterized by excessive interferon signaling and T cell activation. Aim 2 will identify mechanistic risk factors for MIS-C. The proposed studies will test the hypothesis that, even in the absence of infection, circulating immune cells from overweight and obese children exhibit an increased interferon signature that promotes T cell activation. We will develop a strategy for stratifying MIS-C by integrating genetic screening with measures of body mass index. Building on collaborations spanning over a decade and unique cohorts of children with MIS-C and/or obesity, our investigator team brings expertise in MIS-C, host immunity, pediatric obesity and endocrinology, and multiomics. This project will generate causal insights of how overweight and obesity influence the development and severity of MIS-C, with the goal of developing strategies for a population that remains at risk for this disease.

项目摘要/摘要 不可预测性是儿童多系统炎症综合征的标志（MIS-C）。 MIS-C是一个 SARS-COV-2感染的严重小儿并发症。 MIS-C与Covid-19不同。它没有关联 患有预先存在的心肺，自身免疫或血液学疾病。它可以在急性期发生 带有可检测的SARS-COV-2病毒，或在急性感染后几周的感染后期。温和 MIS-C的症状包括发烧，皮疹和胃肠道症状，但可以发展为细胞质， 凝血病，心肌功能障碍，冠状动脉瘤和/或震动。我们和其他人发现这是错误的 C与小儿超重和肥胖有关，从而确定了超过3.8亿儿童有风险 疾病。超重和肥胖影响MIS-C的发展的机制未知。 在所有儿童在全球范围内使用针对SARS-COV-2的疫苗之前，他们将仍然容易受到MIS-C的影响。 我们的初步研究表明，MIS-C是一种高度炎症性疾病，促使更严重 免疫细胞激活比COVID-19，特别是在超重和肥胖的儿童中。超重和肥胖 MIS-C的儿童的T细胞淋巴细胞减少和T细胞激活比正常体重对应的儿童更多， 表明患有更严重疾病的风险增加。有害的遗传变异增加了IFN和 在MIS-C的患者而不是严重的Covid-19患者中，仅发现炎症信号传导。这是一个 与成人严重的Covid-19相关的IFN信号传导有缺陷的机械对位。我们的中心 假设是小儿超重和肥胖素干扰素信号传导，从而增加了T细胞 激活，最终是MIS-C的风险 AIM 1将阐明小儿超重和肥胖如何在MIS-C期间驱动免疫细胞功能障碍。 拟议的研究将检验小儿超重和肥胖与更多相关的假设 严重的MIS-C，其特征是干扰素信号传导和T细胞激活过多。 AIM 2将确定MIS-C的机械风险因素。拟议的研究将检验以下假设： 即使在没有感染的情况下，超重和肥胖儿童的循环免疫细胞也表现出 增加了干扰素特征，促进T细胞激活。我们将制定一项策略来对MIS-C进行分层 与体重指数的度量相结合的遗传筛查。 建立在十多年的合作和独特的MIS-C和/或肥胖的儿童的基础上， 我们的研究人员团队带来了MIS-C，宿主免疫，小儿肥胖和内分泌学的专业知识，以及 多组学。该项目将对超重和肥胖如何影响发展产生因果见解 MIS-C的严重性，目的是为仍处于这种疾病风险的人群制定策略。