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: 10624885
• 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/10624885
• 关键词: Abbreviations; 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; 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; Intubation; Learning; Leukocytes; Link; Live Birth; Longevity; Lung; Lung infections; Medical; Morbidity - disease rate; Mus; Nasopharynx; Pathway interactions; Patients; Persons; Phenocopy; Phenotype; Pneumonia; Population; Predisposition; Publishing; Quality of life; Receptor Gene; Recurrence; Respiratory Disease; Respiratory Tract Infections; Severities; Severity of illness; Signal Transduction; Streptococcus pneumoniae; Testing; Therapeutic Agents; Trisomy; Viral; Virus Diseases; 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; pharmacologic; reconstitution; respiratory; response; 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.

项目概要 唐氏综合症 (DS) 或人类三体综合症，在全世界的活产儿中发病率为 700-1000 分之一 21号染色体（Hsa21）是最常见的染色体异常。虽然 DS 最常被认可为 智力障碍、先天畸形和畸形特征，它还与严重的 呼吸道感染的发生率和严重程度增加。事实上，DS 患者患有传染性呼吸道疾病 占住院人数的 54%，死亡人数比任何其他疾病都多。 DS 儿童 肺炎发生率比没有 DS 的儿童高 62 倍(1)。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 的患者只有 0.1% 死亡。总的来说，这些数据 表明迫切需要了解 21 三体症如何导致呼吸道传染病 并确定潜在的治疗靶点。目前，DS 中的传染性呼吸道疾病通常归因于 鼻咽和上、下呼吸道的先天性异常。不过，我们的初步数据 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 DS 中传染性呼吸道疾病的研究。我们的数据表明，三体 Dp16 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。这些变化非常模仿 人类肺部细胞因子反应失调，这在流感感染后早已观察到， 这种状态与致命细菌性肺炎的易感性增加有关。重要的是，Dp16 小鼠是三体性的 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 DS 肺驱动中干扰素信号传导和 IL-10 信号传导的组成性激活状态 免疫抑制并使 DS 患者易患肺炎链球菌肺炎。该状态表型 在非 DS 个体中观察到的肺炎链球菌肺炎易感性和严重程度增加 经过一个病毒感染过程后。与传染性呼吸道疾病相关的高发病率和死亡率 对于 DS 患者来说，这是一个被严重忽视的医疗需求领域。此外，慢性肺部疾病也日益增多。 与认知缺陷有关。将 DS 概念化为病毒感染后对细菌感染的易感状态 挑战现有的先天性异常范式。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免疫抑制的频率和严重程度 疾病虽然风险很高，但如果成功，将带来高回报，提高人们的健康和寿命 有和没有DS。