Development of lung T cell responses in infant respiratory immunity

项目摘要 SARS-CoV-2的出现导致了全球性的大流行。感染SARS-CoV-2会导致 从无症状和轻度/自限性疾病到重度疾病的疾病症状谱 与严重的肺损伤和高水平的发病率和死亡率相关。就像所有人一样 对这种病毒免疫学上是幼稚的，目前没有针对SARS的靶向治疗或疫苗- CoV-2，保护和恢复取决于我们自己的免疫反应和支持性临床护理。起初， 儿童经历了大部分无症状或轻度疾病，严重疾病导致显著的肺部 伤害是罕见的。然而，一种新的儿童多系统炎症性疾病（MIS-C）与以下疾病有关： SARS-CoV-2已成为感染的晚期并发症。患有MIS-C的儿童通常会出现 心功能不全和休克，最类似于川崎和中毒性休克综合征。 重要的是，一些患有MIS-C的儿童被报道患有冠状动脉瘤， 发现共同的川崎病。儿童中轻度/自限性疾病的显著数量与 与SARS-CoV-2相关的过度炎症表明了不同的免疫反应。 此外，早期感染的长期影响，特别是对心血管系统的影响， SARS-CoV-2仍然未知。我们假设这些不同的临床表现在儿童，包括 SARS-Cov-2呼吸道感染症状的缺乏是由于T细胞应答的强有力和增强。的 该提案的目的是：1）建立儿科患者队列，以比较结果和免疫 儿童COVID-19疾病谱的免疫反应，2）定义儿童免疫反应， SARS-CoV-2及其在疾病临床谱中的差异，以及3）定义 与MIS-C儿童持续不良心脏结局相关的患者特征， 儿科COVID-19。该项目旨在为儿科免疫和长期免疫提供新的见解。 SARS-CoV-2感染的并发症，采用多学科方法，利用一个团队， 研究者包括免疫学家、儿科医生和儿科专科医生（心脏病学/重症监护 医学）。这些研究将提供宝贵的见解，将有助于指导未来的治疗决策 和儿童预防策略。

PROJECT SUMMARY The emergence of SARS-CoV-2 has resulted in a worldwide pandemic. Infection with SARS-CoV-2 causes a spectrum of disease symptoms ranging from asymptomatic and mild/self-limited disease, to severe disease associated with significant lung damage and high levels of morbidity and mortality. As all individuals are immunologically naïve to this virus and there are currently no targeted treatments or vaccines against SARS- CoV-2, protection and recovery depend on our own immune responses and supportive clinical care. Initially, children experienced largely asymptomatic or mild disease with severe disease resulting in significant lung injury a rare occurrence. However, a new multisystem inflammatory disorder in children (MIS-C) related to SARS-CoV-2 has emerged as a late complication of infection. Children with MIS-C commonly present with cardiac dysfunction and shock, most closely resembling Kawasaki disease and toxic shock syndrome. Importantly, some children presenting with MIS-C have been reported to develop coronary artery aneurysms, a finding common to Kawasaki disease. The significant amount of mild/self-limited disease in children contrasted with the excessive inflammation associated with SARS-CoV-2 suggests distinct immune responses. Additionally, the long-term implications, particularly to the cardiovascular system, of early life infection with SARS-CoV-2 remain unknown. We hypothesize that these distinct clinical manifestations in children, including lack of symptomatic respiratory infection to SARS-Cov-2 is due to a robust and enhanced T cell response. The aims of this proposal are to 1) Establish pediatric patient cohorts for comparing outcomes and immune responses across the spectrum of pediatric COVID-19 disease, 2) Define the pediatric immune response to SARS-CoV-2 and how it differs across the clinical spectrum of disease, and 3) Define the incidence of and patient characteristics associated with sustained adverse cardiac outcomes for children with MIS-C and pediatric COVID-19. This project proposes to provide new insights into the pediatric immune and long-term complications of SARS-CoV-2 infection by employing a multi-disciplinary approach utilizing a team of investigators including immunologists, pediatricians, and pediatric subspecialists (cardiology/critical care medicine). These studies will provide invaluable insight that will help guide future decision making for treatment and preventative strategies for children.