Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome

项目总结 全球每700-1000名活产儿中就有一人患有唐氏综合症(DS)，即人类三体 21号染色体(Hsa21)，是最常见的染色体异常。虽然DS是最常被识别的 对于智力残疾、先天畸形和畸形特征，它也与严重的 呼吸道感染(RTI)的发生率和严重性增加。事实上，传染性呼吸道疾病在那些 DS占住院人数的54%，死亡人数比其他任何疾病都多。儿童 患有DS的儿童的肺炎发病率是没有DS的儿童的62倍。在甲型H1N1流感期间 2009年，患有DS的住院患者中有23%死亡，而没有DS的住院患者中只有0.1%死亡。总而言之， 这些数据表明，迫切需要了解21三体的状况如何影响RTI和 确定潜在的治疗靶点。目前，DS的RTI通常被归因于先天性的 鼻咽、上呼吸道和下呼吸道。然而，我们的初步数据支持这一新的假设 肺免疫细胞功能障碍是DS患者RTI发生率和严重程度增加的主要驱动因素。我们的数据 显示Dp16三体小鼠肺处于干扰素病变状态，且缺乏与支气管相关的 淋巴组织(BALT)。BALT是多种免疫和炎症反应的关键控制者 多种刺激，包括RTI。Dp16小鼠肺中的这些变化与失调的 人肺中的细胞因子反应，在流感感染后长期观察到，是一种状态 与致死性细菌性肺炎的易感性增加有关。重要的是，Dp16小鼠是三体 HSA21编码干扰素受体和干扰素反应基因。基于这些数据，我们建议测试 我们的假设是，DS肺中干扰素信号的结构性激活状态降低了BALT 因此，生物发生给予免疫抑制和对肺炎链球菌呼吸道感染的易感性。 这种状态表现为肺炎链球菌呼吸道感染的易感性和严重性增加， 在病毒感染一个疗程后，在典型的个体中观察到。呼吸道感染合并贫困患者病死率高 对疫苗接种的反应是DS的一个紧迫的医疗需求。我们的新范式将DS概念化为 对RTI易感性增加的干扰素病状态，原因是模拟 典型人群中的急性病毒感染状态。作为对NIH的直接回应，包括RFA，我们的 建议是在DS动物模型中进行的概念验证研究，具有高潜在回报，旨在 唐氏综合征和RTI候选疗法的有效和有效的临床试验。

PROJECT SUMMARY With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized for intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously increased rates and severity of respiratory tract infection (RTI). Indeed, infectious respiratory disease in those with DS accounts for 54% of hospital admissions and more deaths than any other medical condition. Children with DS have a 62-fold higher rate of pneumonia than children without DS. During the influenza A (H1N1) pandemic in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively, these data point to an urgent need to understand how the condition of trisomy 21 contributes to RTI and to identify potential therapeutic targets. Currently, RTI in DS is commonly attributed to congenital abnormalities of the nasopharynx and upper and lower airways. However, our preliminary data support the novel hypothesis that lung immune cell dysfunction is a primary driver of increased incidence and severity of RTI in DS. Our data show that the trisomic Dp16 mouse lung is in a state of interferonpathy and is deficient in bronchus-associated lymphoid tissue (BALT). BALTs are key controllers of a variety of immune and inflammatory responses to numerous stimuli, including RTI. These changes in the Dp16 mouse lung closely mimic the dysregulated cytokine response in the human lung that has long been observed following influenza infection, and is a state linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic for the Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we propose to test our hypothesis that the constitutive activation state of interferon signaling in the DS lung reduces BALT biogenesis thus imparting immune suppression and predisposition to respiratory infection with S. pneumoniae. This state phenocopies the increased susceptibility to and severity of S. pneumoniae respiratory infection that is observed in typical individuals after a course of viral infection. The high mortality of RTI combined with poor response to vaccination is an urgent medical need in DS. Our novel paradigm conceptualizes DS as an interferonopathic state of heightened susceptibility to RTI due to depressed BALT function that mimics the state of acute viral infection in the typical population. In direct response to the NIH INCLUDE RFA, our proposal is a proof of concept study in an animal model of DS with high potential payoff that aims to enable efficient and effective movement of candidate therapeutics towards clinical trials for Down syndrome and RTI.