This core will facilitate the validation of mouse data in human cohorts through interactions with each project and by pursuing the characterization of human BCG responses and susceptibility to TB disease. The primary goal is to understand how human genetic variation regulates macrophage immune responses to Mtb infection, in vivo T-cell responses to BCG vaccination, Mtb strain type associations with pulmonary TB, and overall clinical susceptibility to TB. Over the past 10 years in Seattle, we used genetic studies to discover and characterize common human Toll-like Receptor (TLR) pathway polymorphisms which regulate macrophage and dendritic cell cytokine secretion and other host-defense pathways. Similar to gene deletion studies in mice, these au naturel polymorphisms enable us to examine deficiencies of human innate immunity genes and assess their role in ex vivo cellular function, in vivo vaccine T-cell responses, and clinical susceptibility to TB disease. In Core B, we will examine candidate TB susceptibility genes identified in Projects 1 to 3. We will determine whether candidate mouse TB susceptibility genes contain DNA variants which are functional and control replication of MTb in infected macrophages. Using a candidate gene case-control study, determine whether mouse TB susceptibility genes are associated with susceptibility to adult pulmonary TB disease in Vietnam, BCG-induced T-cell responses in South Africa, and/or pediatric TB disease in South Africa. We hypothesize that selected DNA variants in candidate TB susceptibility genes are associated with TB disease and BCG vaccine responses, control gene expression and/or protein function and mediate an effective anti- microbial macrophage response to Mtb infection. With a multidisciplinary team of epidemiologists, geneticists, and immunologists with over 10 years of collaborative work together, we propose to couple genetic and cellular analysis of Mtb-infected human macrophages and human clinical cohorts to discover the mechanisms of how common human genetic variation regulates BCG-induced immune responses and susceptibility to TB.
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