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

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是一种 SARS-CoV-2感染的严重儿科并发症。MI-C有别于新冠肺炎。它没有关联 既有心肺、自身免疫或血液系统疾病。它可以发生在急性期 在可检测到SARS-CoV-2病毒的情况下，或在急性感染后几周内。更温和 MISC的症状包括发烧、皮疹和胃肠道症状，但可进展为细胞减少症， 凝血功能障碍、心肌功能障碍、冠状动脉瘤和/或休克。我们和其他人都发现了- C与儿童超重和肥胖有关，因此确定了超过3.8亿儿童有此风险 疾病。超重和肥胖影响MIS-C发展的机制尚不清楚。 在全球所有儿童都能获得针对SARS-CoV-2的疫苗之前，他们仍将容易感染MISC。 我们的初步研究表明，MIS-C是一种高度炎症性疾病，它会引发更严重的 免疫细胞活化作用优于新冠肺炎，特别是在超重和肥胖儿童中。超重和肥胖 与正常体重的儿童相比，患有MIS-C的儿童有更多的T细胞淋巴细胞减少和T细胞激活， 这表明患更严重疾病的风险增加。有害的基因变异增加了干扰素和 炎症信号仅见于MISC患者，而不是严重新冠肺炎患者。这是一个 与成人严重新冠肺炎相关的干扰素信号缺陷的机械论对策。我们的中央 假设是儿童超重和肥胖启动了干扰素信号，从而增加了T细胞 激活和最终，管理信息系统-C的风险 目的1将阐明儿童超重和肥胖是如何导致免疫细胞功能障碍的。 这项拟议中的研究将检验以下假设：儿童超重和肥胖与 严重的MIS-C，以干扰素信号过度和T细胞激活为特征。 目标2将确定管理信息系统-C的机械性风险因素。拟议的研究将检验这一假设， 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 增强干扰素签名，促进T细胞激活。我们将制定一种对管理信息系统C进行分层的策略 将基因筛查与体重指数测量相结合。 在十多年的合作和独特的MISC和/或肥胖症儿童队列的基础上， 我们的研究团队带来了管理信息系统-C、宿主免疫、儿童肥胖和内分泌学方面的专业知识，以及 多重组学。这个项目将产生对超重和肥胖如何影响发育的因果洞察。 和严重的管理信息系统-C，目标是为仍然处于这种疾病风险中的人群制定战略。

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.