Genetic Epidemiology of Nontuberculous Mycobacteria for Predicting Host Specificity and Lung Disease Outcomes

非结核分枝杆菌(NTM)，包括脓肿分枝杆菌(MAB)和 禽分枝杆菌复合体(MAC)是引起人类肺部疾病的条件致病菌。 流行病学研究表明，肺部NTM感染的患病率不断上升，特别是在个人中 患有囊性纤维化(CF)和50岁以上非囊性纤维支气管扩张症的成年人。只有40%-50%的患者患有 呼吸道NTM培养阳性进展为活动性肺部疾病。因此，治疗的临床决定是 考虑到NTM对大多数类别的抗生素都有抗药性，而且治疗持续一年或更长时间， 不同的成功和药物毒性。在病原体方面，人们对这种病毒的遗传变异性知之甚少 与世隔绝的人口，以及疾病的传播知之甚少。在MAB中，最近的基因组研究 建议在慢性阻塞性肺病诊所内进行人与人之间的传播，从而显著提高公共卫生水平 担忧。在非传染性非传染性疾病病例中占大多数的非传染性非传染性疾病中，没有人群基因组学 到目前为止的研究。这里提出的工作将提供对基因的基础理解 从临床分离株全基因组序列(WGS)数据分析MAB和MAC的流行病学 来自一项正在进行的CF患者研究(n=600)的队列，并为 来自非慢性肝病患者的分离株(n=300)。将对基因组多态性进行评估，并将菌株 临床MAB和MAC群体中的亚型将被确定为组合分离株队列(CF和 非CF)。然后，菌株亚型将与患者的临床变量进行统计关联，包括 年龄、性别、肺功能、合并铜绿假单胞菌感染、CF诊断和活动性肺 以检验某些基因亚型优先感染患者亚群的假设。在一个 更详细的分析，患有NTM的CF患者将按感染状态(短暂、惰性或 活动性肺病)基于美国胸科学会的疾病标准来检验这一假设 一个或多个菌株亚型是发展为活动性NTM肺部疾病的预测个体。 这项研究的结果将是重要的，因为它们将为改进 高危患者人群中新出现病原体的诊断和治疗。拟议的研究 战略和全面职业发展培训计划建立在PI以前#年培训的基础上 分子和计算生物学，以获得人类流行病学、统计遗传学方面的专业知识 和临床结果研究。PI将由一位知名的遗传流行病学家和一位 国家犹太人健康中心无与伦比的研究环境中的CFM和NTM疾病临床专家 全国领先的呼吸系统医院(NJH)。PI处于独特的地位，可以成为一个成功的， 在生物医学研究中的独立研究员，因为建立了完整的临床和研究 NJH的基础设施，NJH是NTM、CF和其他肺部疾病的国家转诊中心。

Nontuberculous mycobacteria (NTM), including Mycobacterium abscessus (MAB) and species in the Mycobacterium avium complex (MAC), are opportunistic pathogens that cause human lung disease. Epidemiological studies show increasing prevalence of pulmonary NTM infections, especially in individuals with cystic fibrosis (CF) and adults over 50 with non-CF bronchiectasis. Only 40-50% of patients with positive respiratory NTM cultures progress to active lung disease. Therefore, the clinical decision to treat is difficult given that NTM are resistant to most classes of antibiotics, and treatment lasts a year or more with varying success and drug toxicities. On the pathogen side, very little is known about the genetic variability of the isolate population, and disease transmission is poorly understood. In MAB, recent genomic studies suggest the possibility of person-to-person transmission within CF clinics raising significant public health concerns. In MAC, which comprise the majority of NTM cases, there have been no population genomics studies to date. The work proposed here will provide a foundational understanding of the genetic epidemiology of MAB and MAC by analyzing whole genome sequence (WGS) data of a clinical isolate cohort from an ongoing study in CF patients (n=600) and also generating a comparable WGS dataset for isolates derived from non-CF patients (n=300). Genomic polymorphisms will be evaluated, and strain subtypes within clinical MAB and MAC populations will be identified for the combined isolate cohort (CF and non-CF). Then, the strain subtypes will be statistically associated with patient clinical variables including age, gender, lung function, co-infection with Pseudomonas aeruginosa, CF diagnosis and active lung disease to test the hypothesis that certain genetic subtypes preferentially infect patient subpopulations. In a more detailed analysis, CF patients with NTM will be stratified by infection status (transient, indolent or active lung disease) based on the American Thoracic Society's criteria for disease, to test the hypothesis that one or more strain subtypes are predictive of individuals who progress to active NTM lung disease. Results from this study will be significant because they will provide a mechanistic basis for improved diagnosis and treatment of emerging pathogens in high-risk patient populations. The proposed research strategy and comprehensive career development training plan build on the PI's previous training in molecular and computational biology in order to gain expertise in human epidemiology, statistical genetics and clinical outcomes research. The PI will be co-mentored by an established genetic epidemiologist and a clinical expert in CF and NTM diseases in the unparalleled research environment at National Jewish Health (NJH), the nation's leading respiratory hospital. The PI is uniquely positioned to become a successful, independent investigator in biomedical research due to the established, integrated clinical and research infrastructure at NJH, a national referral center for NTM, CF and other pulmonary diseases.