Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity 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最常被认为是 智力残疾、先天畸形和畸形特征，也与严重的 呼吸道感染的比率和严重程度增加。事实上，DS患者中的传染性呼吸道疾病 占住院人数的54%，死亡人数比其他任何疾病都多。患有DS的儿童 肺炎发病率是无DS儿童的62倍(1)。在甲型H1N1流感大流行期间 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。总的来说，这些数据 指出迫切需要了解21三体的状况是如何导致呼吸道传染病的 并确定潜在的治疗靶点。目前，DS的传染性呼吸道疾病通常被归因于 到鼻咽和上下呼吸道的先天性异常。然而，我们的初步数据 支持新的假设，即免疫细胞功能障碍是发病率和严重性增加的主要驱动因素 DS中传染性呼吸道疾病的发病率。我们的数据显示，三体Dp16小鼠肺中有更高水平的 干扰素和免疫抑制细胞因子白介素10。这些变化紧密地模仿了 流感感染后长期观察到的人类肺部细胞因子反应失调， 而且是一个与致命性细菌性肺炎易感性增加有关的州。重要的是，Dp16小鼠是三体 Hsa21编码的干扰素受体和干扰素反应基因。根据这些数据，我们 假设干扰素信号和IL-10信号在DS肺驱动中的结构性激活状态 免疫抑制和易患肺炎链球菌肺炎的个体。这种状态的现象学 在非DS患者中观察到肺炎链球菌肺炎的易感性和严重性增加 在病毒感染一个疗程后。与传染性呼吸道疾病相关的高发病率和高死亡率 对于DS患者来说，这是一个严重被忽视的医疗需求领域。此外，慢性肺部疾病日益增多。 与认知缺陷有关。将DS概念化为对细菌感染敏感的病毒后状态 挑战现有的先天畸形范例。建议了解所涉及的机制 免疫抑制，并确定治疗靶点和药物，以改善频率和严重程度 疾病虽然风险很高，但如果成功，将为提高人们的健康和寿命提供高回报 使用和不使用DS。

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 infection. 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(1). 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 respiratory infectious disease and to identify potential therapeutic targets. Currently, infectious respiratory disease 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 immune cell dysfunction is a primary driver of increased incidence and severity of infectious respiratory disease in DS. Our data show that the trisomic Dp16 mouse lung has higher levels of interferons and the immunosuppressive cytokine Interleukin (IL)-10. These changes 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 hypothesize that the constitutive activation state of interferon signaling and IL-10 signaling in the DS lung drives immune suppression and predisposes individuals with DS to S. pneumoniae pneumonia. This state phenocopies the increased susceptibility and severity of S. pneumoniae pneumonia that is observed in non-DS individuals after a course of viral infection. The high morbidity and mortality associated with infectious respiratory disease is a seriously neglected area of medical need for people with DS. In addition, chronic lung disease is increasingly associated with cognitive deficit. Conceptualizing DS as a post-viral state of susceptibility to bacterial infection challenges the existing paradigm of congenital abnormality. Proposing to understand the mechanisms involved in immune suppression and to identify therapeutic targets and agents to ameliorate frequency and severity of disease, while high risk, would, if successful, provide a high payoff in the increased health and longevity of people with and without DS.