A multi-disciplinary approach to the identification of host metabolic determinan

虽然只有少数感染结核分枝杆菌的个体进展为活动性疾病， 与进展相关的宿主因素知之甚少。最近的数据显示， 低体重指数、代谢综合征和2型糖尿病等因素是强有力的预测因子 一个人在感染后发展为活动性疾病的风险。越来越多的证据表明， 个体代谢状态与人类巨噬细胞和树突细胞活化控制之间的联系 和分化途径。在这里，我们建议确定结核病涉及的关键宿主代谢途径 在现有结核病暴露队列的遗传研究中， 在人类中进行观察研究，在豚鼠模型中进行干预研究。一是 利用我们现有的经微生物学证实的结核病指标病例队列及其暴露、感染 家庭接触者在接触后两年内没有患病。使用嵌套案例 对照研究设计，我们将评估已知影响关键代谢特征的遗传变异的影响， 以及使用针对秘鲁人优化的外显子组芯片对结核病进展进行罕见的编码变异 我们工作的人群。其次，我们将使用本研究的结果来指导进一步验证这些 通过对来自病例和暴露的非疾病的人髓样细胞的转录谱分析确定 对照在一个子研究中，我们还将这些外显子组芯片和转录谱数据来鉴定基因 通过与CD 1、白细胞介素-1和NF κ B相关的基因评估，参与树突状细胞成熟。到 进一步探索这些代谢和免疫途径的影响，我们将进行结核病感染 通过饮食和药理学改变豚鼠代谢状态的实验 干预措施，目的是确定可能的治疗干预措施，可以转移到人体试验， 未来的工作。

Although only a minority of individuals infected with Mycobacterium tuberculosis progress to active disease, host factors associated with progression are only poorly understood. Recent data show that metabolic risk factors such as low body-mass index, metabolic syndrome and type 2 diabetes mellitus are strong predictors of an individual's risk of progressing to active disease after infection. Further, growing evidence suggests a link between an individual's metabolic state and control of human macrophage and dendritic cell activation and differentiation pathways. Here, we propose to identify key host metabolic pathways involved in TB progression in a genetic study of an existing TB exposed cohort and then test these associations by performing observational studies in humans and intervention studies in guinea pig models. First, we will leverage our existing cohort of microbiologically confirmed TB index cases and their exposed, infected household contacts who have remained disease free for two years after exposure. Using a nested case control study design, we will assess the impact of genetic variants known to affect key metabolic traits as well as rare coding variants on TB progression using exome chips that are optimized for the Peruvian population in which we work. Second, we will use the results of this study to guide further validation of these determinants through transcriptional profiling of human myeloid cells from cases and exposed non-diseased controls. In a sub-study, we will also these exome chip and transcriptional profiling data to identify the genes involved in dendritic cell maturation as assessed by genes related to CD1, interleukin-1 and NFkappaB. To further explore the impact of these metabolic and immune pathways, we will conduct TB infection experiments in guinea pigs in which metabolic status is modified through dietary and pharmacological interventions with the aim of identifying possible therapeutic interventions that could moved to human trials in future work.