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

• 批准号: 10591411
• 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
• 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/10591411
• 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 Gene; 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; Upper respiratory tract; 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; improved; 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

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.

总结 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 通常使人衰弱的肺病需要复杂和广泛的多种药物抗生素治疗， 终身的此外，50%的培养转阴的治疗患者会复发， 无论是现有的感染还是新的感染。NTM在环境和人类中普遍存在， 由于在整个生命过程中经常接触到这种物质，肺病几乎只发生在老年人中。是 因此，肺NTM疾病的发病率和患病率增加并不奇怪，这反映了 美国整体年龄结构的变化NTM易感性增加的潜在机制 疾病与年龄的关系还不清楚。因此，在这方面的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理解。这就更加紧迫了 研究领域的事实是，美国人口普查局估计，到2030年，超过20%的美国居民 预计年龄至少在65岁以上。在本申请中，我们提出检验中心假设 老年人更容易患NTM疾病，这是由于Th1 T细胞免疫缺陷， 肺部微生物组失调，有利于病原菌的获得。为此我们 将利用高度翻译的恒河猴模型，首先确定年龄相关的变化， 免疫学参数、炎症标志物和微生物群落。然后，我们将利用一本小说 我们小组建立的恒河猴模型概括了肺MAC疾病的特征， 开展实验性前瞻性研究，以揭示年龄介导的免疫反应和肺功能的改变。 与慢性NTM肺结核易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制的新见解， 老年人的发病率显著增加，随着美国人口的增加， 人口老龄化。识别与疾病保护或风险相关的免疫或微生物组可能导致 直接改善这些患者的临床护理和预防老年人的这种疾病。