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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结