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.
Although human metabolic risk factors are emerging as strong predictors of TB suscepfibility, the mechanisms through they affect the risk and severity of disease have not been eludicated. A better understanding ofthe molecular pathways that link metabolic and immune responses might provide targets forthe development of therapeutic intervenfions. Here, we use human genefic and transcripfional studies and a guinea pig model to explore these pathways.
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