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

唐氏综合症细菌性肺炎易感性和严重程度的持续病毒感染后状态

• 批准号: 10177857
• 负责人: MICHAEL E. YEAGER
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177857
• 关键词: Acute; Address; Adult; Area; Attenuated; Bacterial Infections; Bacterial Pneumonia; Biological Markers; Blood; Bone Marrow Ablation; Cells; Cessation of life; Child; Chromosome 21; Chromosome abnormality; Chronic; Chronic lung disease; Cognitive deficits; Communicable Diseases; Congenital Abnormality; Data; Development; Disease; Down Syndrome; Etiology; Eye; Frequencies; Functional disorder; Gene Expression Profile; Genes; Health; Hospital Mortality; Hospitalization; Human; Human Chromosomes; Immune; Immune system; Immunosuppression; Incidence; Individual; Infection; Infectious Lung Disorder; Influenza A Virus, H1N1 Subtype; Influenza A virus; Intellectual functioning disability; Interferon Activation; Interferon Receptor; Interferons; Interleukin-10; Learning; Leukocytes; Link; Live Birth; Longevity; Lung; Lung diseases; Lung infections; Medical; Morbidity - disease rate; Mus; Nasopharynx; Pathway interactions; Patients; Persons; Pharmacology; Phenocopy; Phenotype; Pneumonia; Population; Predisposition; Publishing; Quality of life; Receptor Gene; Recurrence; Respiratory Tract Infections; Severities; Severity of illness; Signal Transduction; Streptococcus pneumoniae; Testing; Trisomy; Virus Diseases; base; cell type; clinically significant; cytokine; dosage; high risk; improved; influenza infection; interleukin-10 receptor; mortality; mouse model; neglect; novel; novel therapeutics; pandemic disease; pandemic influenza; peripheral blood; reconstitution; respiratory; response; targeted agent; therapeutic target

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.

项目摘要 全球700-1000个活产的发生率是唐氏综合症（DS）或人类三体性的发生率 染色体21（HSA21）是最常见的染色体异常。虽然DS最常被认可 智力残疾，先天性畸形和畸形特征，它也与 呼吸道感染的发生率和严重程度增加。确实，DS患者感染性呼吸道疾病 占住院入院的54％，死亡人数比任何其他医疗状况都要多。患有DS的孩子 肺炎的发生率比没有DS（1）的儿童高62倍。在流感A（H1N1）大流行期间 2009年，有23％的住院DS患者死亡，而没有DS的患者中只有0.1％。这些数据集体 指出迫切需要了解21三体疾病如何导致呼吸道传染病 并确定潜在的治疗靶标。目前，DS中的传染性呼吸道疾病通常归因于 鼻咽和上和下气道的先天性异常。但是，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程度增加的主要驱动力 DS中的传染性呼吸道疾病。我们的数据表明，Trisomic DP16小鼠肺有更高的水平 干扰素和免疫抑制细胞因子白介素（IL）-10。这些变化紧密模仿 人类肺中的细胞因子反应失调，在流感感染后长期观察到， 并且是与增加致命细菌性肺炎敏感性有关的状态。重要的是，DP16小鼠是trisomic 用于HSA21编码的干扰素受体和干扰素反应基因。基于这些数据，我们 假设干扰素信号传导和IL-10信号传导的组成型激活状态 免疫抑制和容易患有DS的个体患肺炎链球菌。这种状态的表演 在非DS个体中观察到的肺炎链球菌的敏感性和严重程度增加 经过病毒感染的过程。与感染性呼吸系统疾病有关的高发病率和死亡率 对于患有DS的人来说，这是一个被严重忽视的医疗需求领域。此外，慢性肺病越来越多 与认知不足有关。将DS概念化为细菌感染易感性的病毒后状态 挑战现有的先天性异常范式。建议了解所涉及的机制 在免疫抑制并确定治疗靶标和药物以改善频率和严重程度 疾病虽然很高的风险，但如果成功，疾病将在健康和寿命增加的情况下带来高昂的回报 有和没有DS。