Tuberculosis (TB), caused by M. tuberculosis (Mtb), is a significant, global public health problem, particularly in sub-Saharan Africa, where the prevalence of TB is increasing dramatically with the rise of the HIV pandemic. Previous studies provide strong evidence that host genetic factors contribute to the risk for TB disease; those studies identified potential candidate genes, but no consensus model for the genetic susceptibility to TB has yet emerged, and no studies have examined genetic influences on the early stages of Mtb infection. The present proposal utilizes patients and data collected through the Tuberculosis Research Unit (TBRU) NIH contract. Since 1995, we have been conducting a household contact study in Uganda where we are able to observe genetic and environmental risk factors for chronic Mtb infection and active TB disease. Our previous work has focused on genetic influences on the immune response and the spectrum of natural history of Mtb infection. We have shown that the TNFR1, IL10, and IFNGR1 genes are associated with TB but not resistance to Mtb infection. We have recently completed a genome scan that identified novel chromosomal regions, 2q21-2q24 and 5p13- 5q22, linked to resistance to Mtb. We have also identified innate immune response variables associated with progression to TB disease, but have not assessed immune factors associated with resistance to Mtb infection. Our preliminary results suggest that genetic and immune factors associated with resistance to Mtb infection versus TB disease development differ. Furthermore, we hypothesize that the complex interrelationships between host genes, innate immune response, and epidemiological factors combine to influence Mtb infection and progression to TB disease. To fully examine this complex network of genes and immune factors, we propose to construct a comprehensive pathway model. To this end, we propose three aims. First, we propose to fine map these novel chromosomal regions and analyze candidate genes in key immune pathways to identify genes associated with resistance to Mtb infection. Second, we propose to analyze a number of cytokines in response to innate immunity ligands to identify aspects of the innate immune response associated with resistance to Mtb infection. Third, we have developed a structural equation modeling framework appropriate for the analysis of family data, and we propose to analyze this data with that model and make software publicly available. We will analyze genetic and immunologic predictors of resistance to Mtb infection within the long-standing household contact study. This will also provide the first examination of resistance to Mtb infection; because of our thorough study design, we are uniquely poised to analyze this novel phenotype. PUBLIC HEALTH RELEVANCE: Tuberculosis (TB) is a disease with great public health importance, with one-third of the world infected by M. tuberculosis (Mtb), and almost 8 million new cases of TB occur annually with 2 million deaths attributed to TB each year. Previous studies have shown a role for both genetic and immunologic factors that predispose to progression from Mtb infection to active TB disease, but these factors have not been analyzed simultaneously and have not identified factors associated with the healthy uninfected state. Findings of this project will expand knowledge of the joint genetic, epidemiologic, and immunologic influences on Mtb infection and TB disease, which will facilitate the development of improved vaccines and therapeutics.