Role of SARS-CoV-2-mediated Type I IFN antagonism in individuals with Down Syndrome

项目摘要 I型干扰素是一种细胞因子，具有很强的抗病毒和促炎活性。因此，他们 受到严格监管，以提供足够的抗病毒作用，同时不会引起过度和破坏健康的炎症。 已知的干扰素调节失调引起的疾病称为I型干扰素病。 唐氏综合征(DS)是导致智力和发育障碍的最常见的遗传原因 儿童和年轻人，在美国的发病率约为每600人中有1人。患有DS的人通常有 心脏和胃肠道异常。此外，它们还存在一些与免疫相关的问题 自身免疫增加了对一系列传染病的易感性。不幸的是，确切的分子 导致这些免疫缺陷的机制尚未阐明。 新冠肺炎是一种由冠状病毒引起的疾病，即严重急性呼吸系统综合症-CoV-2。 SARS-CoV-2的感染现在在全球每个国家都存在，造成了前所未有的公众 健康负担。SARS冠状病毒已知会干扰干扰素-I的诱导和信号传递。SARS冠状病毒在多大程度上- 2在患有DS的个体中是否会导致疾病目前尚不清楚。在大多数情况下，DS是由额外的 21号染色体，编码I型干扰素受体(IFNAR1和IFNAR2)。这是怎么回事 基因剂量效应在SARS-CoV-2的病理生理学中的作用尚不清楚。这项提议是建立在 围绕着IFNAR1和IFNAR2的相对量是控制SARS的基本因素的假设- 冠状病毒2型的病理生理学。为了解决这一假设，我们建议在分子水平对DS患者进行体外研究。 水平，以确定这些基因剂量在调节人类干扰素途径中的功能意义 SARS-CoV-2感染。 在SARS-CoV-2的背景下，更深入地了解干扰素-I在DS中的分子调控将使我们能够 更好地了解如何处理疾病的临床管理。

Project Summary Type I Interferons (IFN-Is) are cytokines with potent anti-viral and proinflammatory activities. As such they are tightly regulated to provide enough antiviral effects while not causing over and health disrupting inflammation. Disorders where IFN-Is dysregulation is known to cause pathology are termed type I Interferonopathies. Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities in children and young adults with Incidence in US of about 1 in 600 individuals. Individuals with DS often have cardiac and gastrointestinal abnormalities. Additionally, they have a number of immune-related problems from increased susceptibility to an array of infectious diseases to autoimmunity. Unfortunately, the exact molecular mechanism leading to these immune defects has not been elucidated. COVID-19 is a disease caused by a coronavirus, Severe Acute Respiratory Syndrome (SARS) -CoV-2. Infections by SARS-CoV-2 are now present in every country around the globe, causing unprecedented public health burden. SARS-CoV is known to interfere with IFN-I induction and signaling. To which extent SARS-CoV- 2 can cause illness in individuals with DS is currently unknown. DS is, in most cases, caused by an extra chromosome 21, on which the receptors for type I Interferons (IFNAR1 and IFNAR2) are encoded. How this gene dosage effects are contributing to SARS-CoV-2 pathophysiology is not understood. This proposal is built around the hypothesis that relative amounts of IFNAR1 and IFNAR2 are the essential factors controlling SARS- CoV-2 pathophysiology. To address this hypothesis, we propose to study DS patients in vitro at the molecular level to determine the functional significance of dose of these genes in regulating IFN pathway in humans during SARS-CoV-2 infection. Deeper understanding of molecular regulation of IFN-I in DS in the context of SARS-CoV-2 will allow us to better understand how to approach clinical management of disease.