Interferon hyperactivity, COVID19, and Down syndrome

项目总结。 这是对我们由美国国立卫生研究院资助的变革性R01奖的紧急竞争性修订的申请 包括名为“将唐氏综合症理解为干扰素病”的项目和NIAID。中环 家长奖的假设是干扰素(干扰素)信号的过度激活导致许多 DS的发育和临床特征。在这次修订中，我们将研究干扰素与 多动、免疫失调、COVID19病理学和对SARS-CoV-2的免疫。我们假设 干扰素的过度活跃将改变DS的临床病程，包括长期免疫学 后遗症，同时可能损害对SARS-CoV-2的细胞和体液免疫的发展。我们的 具体目标是： 1.确定DS患者柯萨奇病毒19的临床和免疫学特征。这一点越来越明显 感染SARS-CoV-2的DS患者更有可能住院，发展为继发性细菌 感染，并在更年轻的时候死亡。然而，关于该病的临床病程仍有许多问题没有回答。 DS中的COVID19。DS患者发生严重COVID19的危险因素是什么？有没有这样的治疗方式 在DS中更有效还是更有效？患有DS的幸存者感染SARS-CoV-2的后遗症是什么？在这里，我们 将采用国家COVID Cohort Collaborative(N3C)、DS-Connect®注册表和Human Trisome 项目(HTP)队列研究，以产生对临床和免疫学特征的最终评估 在DS中的COVID19。我们将完成对N3C数据库和HTP团队获得的数据的并行分析 通过电子健康记录摘要和参与者调查来识别早期症状的差异， 免疫学参数、临床病程、危险因素、对不同治疗方式的反应和长期 后遗症，强调年龄、性别、种族/民族和地理位置的潜在差异。 2.调查一组患有DS的COVID19幸存者的免疫表型。我们广泛的调查 对DS患者免疫表型的研究揭示了T和B细胞谱系的强烈失调，包括 可能损害针对SARS-CoV-2的细胞和体液免疫发展的变化 对SARS-CoV-2疫苗的反应。现在，在DS-Connect®注册中心和HTP队列研究的支持下，我们 将从在SARS-CoV-2感染中幸存下来的DS患者身上获得生物菌素。我们将包括这些 我们正在进行的泛组学研究中的样本描述了DS患者的干扰素过度活动和免疫失调，而 还研究了记忆T和B细胞反应的发展和持续时间以及中和反应的产生 SARS-CoV-2特异性抗体。 总而言之，这些协同目标解决了这一国家安全倡议的多个方面，将促进我们的理解。 21三体和干扰素过度活动对DS患者COVID19的影响 为这一高危人群定制预防、诊断和治疗策略。

PROJECT SUMMARY. This is an application for an Urgent Competitive Revision to our Transformative R01 award funded by the NIH INCLUDE Project and NIAID titled ‘Understanding Down Syndrome as an Interferonopathy’. The central hypothesis of the parent award is that hyperactivation of interferon (IFN) signaling causes many of the developmental and clinical hallmarks of DS. In this revision, we will investigate the interplay between IFN hyperactivity, immune dysregulation, COVID19 pathology, and immunity against SARS-CoV-2. We hypothesize that IFN hyperactivity will modify the clinical course of COVID19 in DS, including long term immunological sequalae, while potentially impairing development of cellular and humoral immunity against SARS-CoV-2. Our Specific Aims are: 1. Determine the clinical and immunological characteristics of COVID19 in DS. It is increasingly evident that individuals with DS infected by SARS-CoV-2 are more likely to be hospitalized, develop secondary bacterial infections, and die at younger ages. However, many questions remain unanswered about the clinical course of COVID19 in DS. What are the risk factors for severe COVID19 in DS? Are there treatment modalities that are less or more effective in DS? What are the sequalae of SARS-CoV-2 infection in survivors with DS? Here, we will employ the National COVID Cohort Collaborative (N3C), the DS-Connect® registry, and the Human Trisome Project (HTP) cohort study to generate a definitive assessment of the clinical and immunological characteristics of COVID19 in DS. We will complete parallel analyses of the N3C database and data obtained by the HTP team via electronic health record abstraction and participant surveys to identify differences in early symptoms, immunological parameters, clinical course, risk factors, response to different treatment modalities, and long term sequalae, with emphasis on potential differences by age, sex, race/ethnicity, and geography. 2. Investigate the immune phenotype of a cohort of COVID19 survivors with DS. Our extensive investigation of the immune phenotype of people with DS has revealed strong dysregulation of T and B cell lineages, including changes that could impair the development of cellular and humoral immunity against SARS-CoV-2 and the response to SARS-CoV-2 vaccines. Now, supported by the DS-Connect® registry and the HTP cohort study, we will obtain biospecimens from individuals with DS that survived SARS-CoV-2 infection. We will include these samples in our ongoing pan-omics characterization of IFN hyperactivity and immune dysregulation in DS, while also investigating the development and duration of memory T and B cell responses and production of neutralizing antibodies specific for SARS-CoV-2. Altogether, these synergistic aims, which address multiple aspects of this NOSI, will advance our understanding of the impacts of trisomy 21 and IFN hyperactivity on COVID19 in DS, thus informing the rapid development of customized preventive, diagnostics, and therapeutic strategies for this at-risk population.