Mechanisms of increased susceptibility to pulmonary Nontuberculous Mycobacterial disease in the elderly

老年人肺非结核分枝杆菌病易感性增加的机制

基本信息

批准号：
10377459
负责人：
Ilhem Messaoudi
金额：
$ 71.25万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-16 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377459
关键词：
Acute Disease Affect Age Age-Years Aged, 80 and over Aging American Animal Diseases Antibiotic Therapy Antibiotics Antibodies Area Biological Assay Biology Cells Censuses Chronic Chronic Disease Chronic lung disease Communities Coupled Cytokine Gene Defect Development Disease Elderly Environment Female Genetic Transcription Genomics Genus Mycobacterium Health Immune Immune response Immunity Immunologics Immunology Immunology procedure Incidence Individual Infection Interferon Type II Interleukin-12 Kinetics Lead Life Lower respiratory tract structure Lung Lung diseases Lung infections Macaca mulatta Mediating Modeling Morbidity - disease rate Mucociliary Clearance Mutation Mycobacterium Infections Mycobacterium avium Mycobacterium avium Complex Mycobacterium avium-intracellulare Infection Mycobacterium tuberculosis Oral Pathogenesis Patient Care Patients Peripheral Blood Mononuclear Cell Physiological Play Population Predisposition Prevalence Prospective Studies Pulmonology Relapse Research Risk Role Severities Severity of illness Statistical Models Structure T-Lymphocyte TNF gene Testing Tuberculosis United States age effect age related aged aging population clinical care cytokine disorder prevention disorder risk exposed human population genome wide association study human old age (65+)immune activation inflammatory marker inhibitor insight juvenile animal lung microbiome lung microbiota mathematical model microbial community microbiome next generation sequencing non-tuberculosis mycobacteria nonhuman primate novel pathogen pathogenic bacteria probiotic therapy pulmonary function respiratory microbiome response virtual

项目摘要

SUMMARY Mycobacterium avium (MAC) and other non-tuberculous mycobacteria (NTM) can cause chronic, insidious and often debilitating lung disease necessitating complicated and extensive multi-drug antibiotic therapy that can be life-long. Additionally, 50% of treated patients who have culture conversion to negative will suffer a relapse of either their existing infection or a new infection. While NTM are ubiquitous in the environment and human exposure throughout life is frequent, pulmonary disease is found almost exclusively among the elderly. It is therefore not surprising that pulmonary NTM disease is increasing in incidence and prevalence, mirroring changes in the overall age structure of the U.S. Mechanisms underlying the increased susceptibility to NTM disease with age are not well understood. Consequently, there is an unmet need in virtually all aspects of this disease and its management, including an understanding of disease pathogenesis. Adding urgency to this research area is the fact that the U.S. Census Bureau estimates that by 2030, more than 20% of the US residents are projected to be at least 65 years old and over. In this application, we propose to test the central hypothesis that aged individuals are more susceptible to NTM disease due to defects in Th1 T cell immunity coupled with dysregulation in lung microbiome that favor the acquisition of pathogenic bacteria. To that end, we will leverage the highly translational rhesus macaque model to first identify age-associated changes in immunological parameters, inflammatory markers and microbial community. Then, we will leverage a novel rhesus macaque model established by our group that recapitulates the hallmarks of pulmonary MAC disease to carry out experimental prospective studies to uncover age-mediated alterations in immune responses and lung microbial communities that are associated with susceptibility to and development of chronic NTM pulmonary disease. These studies will lead to novel insight into the pathogenesis of this chronic lung disease that causes significant morbidity in the elderly and continues to increase in incidence and prevalence as the American population ages. Identification of immune or microbiome correlates of protection or risk of disease could lead directly to improvements in the clinical care of these patients and the prevention of this disease in the elderly.

概括分枝杆菌（MAC）和其他非结核分枝杆菌（NTM）会引起慢性，阴险和经常使肺部疾病衰弱，需要复杂而广泛的多药抗生素疗法终身。此外，有50％的患者在培养为阴性的治疗患者中会复发他们的现有感染或新感染。而NTM在环境和人类中无处不在一生的暴露经常出现，几乎完全在老年人中发现肺部疾病。这是因此，毫不奇怪的是，肺NTM疾病的发病率和患病率正在增加，反映美国对NTM敏感性提高的美国机制的整体年龄结构的变化随着年龄的增长，疾病尚不清楚。因此，几乎所有方面都有未满足的需求疾病及其管理，包括对疾病发病机理的理解。为此增加紧迫性研究领域是美国人口普查局估计，到2030年，美国居民中有超过20％预计至少65岁及以上。在此应用中，我们建议测试中心假设由于Th1 T细胞免疫的缺陷，老年人更容易受到NTM疾病的影响肺微生物组的失调，有利于获取致病细菌。为此，我们将利用高度转化的恒河猕猴模型首先确定与年龄相关的变化免疫学参数，炎症标记和微生物群落。然后，我们将利用小说由我们的小组建立的恒河猕猴模型，将肺MAC疾病的标志概括为进行实验性前瞻性研究以发现年龄介导的免疫反应和肺的改变与慢性NTM肺的敏感性和发展相关的微生物群落疾病。这些研究将导致对这种慢性肺部疾病的发病机理的新洞察美国老年人的发病率很高，并且随着美国的发病率和流行率继续增加人口年龄。免疫或微生物组保护或疾病风险的鉴定可能导致直接改善这些患者的临床护理以及预防老年人的这种疾病。