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.

概括鸟分枝杆菌 (MAC) 和其他非结核分枝杆菌 (NTM) 可引起慢性、隐匿性和经常使人衰弱的肺部疾病需要复杂和广泛的多药抗生素治疗终身。此外，接受治疗的患者中，50% 的培养物转阴后会出现复发现有感染或新感染。虽然 NTM 在环境和人类中普遍存在一生中接触这种物质的情况很频繁，因此肺部疾病几乎只发生在老年人中。这是因此，肺部 NTM 疾病的发病率和患病率不断增加也就不足为奇了，这反映出美国整体年龄结构的变化导致 NTM 易感性增加的机制疾病随年龄增长的情况尚不清楚。因此，几乎所有方面都存在未满足的需求疾病及其管理，包括对疾病发病机制的了解。增加了这件事的紧迫性研究领域是这样一个事实：美国人口普查局估计，到 2030 年，超过 20% 的美国居民预计年龄至少为 65 岁及以上。在此应用中，我们建议检验中心假设由于 Th1 T 细胞免疫缺陷，老年人更容易患 NTM 疾病肺部微生物群失调，有利于致病菌的获得。为此，我们将利用高度转化的恒河猴模型首先识别与年龄相关的变化免疫学参数、炎症标志物和微生物群落。然后，我们将利用小说我们课题组建立的恒河猴模型概括了肺 MAC 疾病的特征进行实验性前瞻性研究，以揭示年龄介导的免疫反应和肺部变化与慢性 NTM 肺病的易感性和发展相关的微生物群落疾病。这些研究将对这种慢性肺部疾病的发病机制产生新的见解。老年人的发病率很高，并且随着美国的发展，其发病率和患病率持续增加人口年龄。识别与保护或疾病风险相关的免疫或微生物组可能会导致直接改善这些患者的临床护理和预防老年人的这种疾病。