Mechanisms of increased susceptibility to pulmonary Nontuberculous Mycobacterial disease in the elderly
Mechanisms of increased susceptibility to pulmonary Nontuberculous Mycobacterial disease in the elderly
批准号:
10377459
负责人:
Ilhem Messaoudi
金额:
$71.25万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-04-16 至 2025-03-31
关键词:
Acute DiseaseAffectAgeAge-YearsAged, 80 and overAgingAmericanAnimal DiseasesAntibiotic TherapyAntibioticsAntibodiesAreaBiological AssayBiologyCellsCensusesChronicChronic DiseaseChronic lung diseaseCommunitiesCoupledCytokine GeneDefectDevelopmentDiseaseElderlyEnvironmentFemaleGenetic TranscriptionGenomicsGenus MycobacteriumHealthImmuneImmune responseImmunityImmunologicsImmunologyImmunology procedureIncidenceIndividualInfectionInterferon Type IIInterleukin-12KineticsLeadLifeLower respiratory tract structureLungLung diseasesLung infectionsMacaca mulattaMediatingModelingMorbidity - disease rateMucociliary ClearanceMutationMycobacterium InfectionsMycobacterium aviumMycobacterium avium ComplexMycobacterium avium-intracellulare InfectionMycobacterium tuberculosisOralPathogenesisPatient CarePatientsPeripheral Blood Mononuclear CellPhysiologicalPlayPopulationPredispositionPrevalenceProspective StudiesPulmonologyRelapseResearchRiskRoleSeveritiesSeverity of illnessStatistical ModelsStructureT-LymphocyteTNF geneTestingTuberculosisUnited Statesage effectage relatedagedaging populationclinical carecytokinedisorder preventiondisorder riskexposed human populationgenome wide association studyhuman old age (65+)immune activationinflammatory markerinhibitorinsightjuvenile animallung microbiomelung microbiotamathematical modelmicrobial communitymicrobiomenext generation sequencingnon-tuberculosis mycobacterianonhuman primatenovelpathogenpathogenic bacteriaprobiotic therapypulmonary functionrespiratory microbiomeresponsevirtual
中文摘要
摘要
禽分枝杆菌(MAC)和其他非结核分枝杆菌(NTM)可引起慢性、隐匿性和
通常使人衰弱的肺部疾病需要复杂和广泛的多种药物抗生素治疗,这种治疗可以
终生如此。此外,50%的培养转为阴性的接受治疗的患者将复发
要么是他们现有的感染,要么是新的感染。而NTM在环境和人类中无处不在
终生接触频繁,肺部疾病几乎只在老年人中发现。它是
因此,肺部NTM疾病的发病率和患病率正在增加并不令人惊讶,这反映了
美国总体年龄结构的变化导致非传染性支气管炎易感性增加的机制
随着年龄增长的疾病还没有得到很好的了解。因此,在这方面几乎所有方面都有未得到满足的需求
疾病及其管理,包括对疾病发病机制的理解。为这件事增加紧迫性
研究领域是,美国人口普查局估计,到2030年,超过20%的美国居民
预计至少65岁及以上。在这个应用程序中,我们建议检验中心假设
由于Th1 T细胞免疫偶联缺陷,老年人更容易患上NTM
肺部微生物群失调,有利于病原菌的获取。为此,我们
将利用高度翻译的恒河猴模型首先确定与年龄相关的变化
免疫学参数、炎症标志物和微生物群落。然后,我们将利用一本小说
本课题组建立的恒河猴模型概括了肺性MAC病的特征,以
进行实验性前瞻性研究,以揭示年龄介导的免疫反应和肺的变化
与慢性非传染性支气管炎肺部易感性和发展相关的微生物群落
疾病。这些研究将为这种慢性肺部疾病的发病机制带来新的见解。
老年人的发病率很高,而且发病率和流行率继续上升,因为美国
人口老龄化。识别免疫或微生物组与保护或疾病风险的相关性可能会导致
直接用于改善这些患者的临床护理和预防老年人的这种疾病。
英文摘要
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.
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