Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome

项目摘要 唐氏综合征（Down Syndrome，DS）或人类染色体三体综合征（Trisomy of human births）的发病率在全世界范围内为700-1000例活产婴儿中的1例。 21号染色体（Hsa 21）是最常见的染色体异常。虽然DS通常被认为是 智力残疾、先天畸形和畸形特征，也与严重的 呼吸道感染的发生率和严重程度增加。事实上，DS患者的传染性呼吸道疾病 占住院人数的54%，死亡人数超过任何其他医疗条件。儿童DS 患肺炎的几率比没有DS的儿童高62倍（1）。在甲型H1N1流感大流行期间 2009年，23%的住院DS患者死亡，而没有DS的患者死亡率仅为0.1%。这些数据共同 指出迫切需要了解21三体的条件如何有助于呼吸道传染病 并鉴定潜在的治疗靶点。目前，DS中的传染性呼吸道疾病通常归因于 鼻咽部和上下呼吸道的先天性异常。然而，我们的初步数据显示， 支持免疫细胞功能障碍是发病率和严重程度增加的主要驱动因素的新假设 传染性呼吸道疾病的发病率我们的数据显示三体Dp 16小鼠肺具有更高水平的 干扰素和免疫抑制细胞因子白细胞介素（IL）-10。这些变化与 长期以来在流感感染后观察到的人肺中失调的细胞因子应答， 并且是一种与增加对致命细菌性肺炎的易感性有关的状态。重要的是，Dp 16小鼠是三体的， Hsa 21编码的干扰素受体和干扰素应答基因。根据这些数据，我们 假设DS肺中干扰素信号传导和IL-10信号传导的组成性激活状态驱动 免疫抑制，并使DS患者易患S。肺炎这种状态模仿 S.在非DS个体中观察到的肺炎 在病毒感染后与传染性呼吸道疾病相关的高发病率和死亡率 是一个严重被忽视的领域的医疗需求的人与DS。此外，慢性肺病越来越多地 与认知缺陷有关。将DS概念化为对细菌感染易感的病毒后状态 挑战了现有的先天性异常的模式。提出要了解所涉及的机制 并鉴定治疗靶点和药剂以改善免疫抑制的频率和严重性。 疾病，虽然高风险，如果成功，将提供一个高回报，在增加人们的健康和寿命 有和没有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.