Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas

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PROJECT SUMMARY/ABSTRACT Immunologically, the enigma of the granuloma is best reflected in that sterile, bacillus-controlling, and progressive granulomas can coexist in the same lung, with the progressive form ultimately killing the host. This observation is consistent with the modern concept of “concomitant immunity: the paradoxical immune status in which resistance to reinfection coincides with the persistence of the original infection”. Here, we will test the hypothesis that the development of concomitant immunity regulates macrophage differentiation, influencing granuloma formation and ultimately the outcome of the battle between the immune response and the pathogen Mycobacterium tuberculosis. To do so, we will use single cell RNA sequencing and spatial sequencing to map the coordinates of cell populations and antimicrobial mediators in human TB granulomas. We propose the following specific aims: 1) elucidate the cellular and molecular architecture of human pulmonary TB granulomas, 2) investigate the role of macrophage subpopulations that contribute to the antimicrobial response vs. pathogenesis of TB granulomas; and 3) investigate the role of T cell subpopulations in contributing to concomitant immunity in TB granulomas. We will identify specific cell subpopulations that contribute to host defense by comparing individual TB granulomas with varying bacterial loads and those with pathogenesis by examining the dynamic change with the progression of primary lesions, to early lesions with bronchial obstruction, to post-primary granulomas. We will determine the role of macrophage subpopulations in host defense and pathogenesis, in particular the foamy macrophages that we discovered express TREM2. We will investigate which T cell populations are predictors of individuals that respond to chemotherapy versus those that are resistant and therefore serve as biomarkers. These studies will bring together collaborators at UCLA, the Ragon Institute and the Institut Pasteur de Tunis with expertise in clinical tuberculosis, immunology and molecular biology to gain new insight into the mechanisms by which concomitant immunity influences granuloma structure to optimize host defense against TB.