Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease

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ABSTRACT - PROJECT 2 Between the initial encounter of Mycobacterium tuberculosis (Mtb) with alveolar macrophages (AM) and the development of active disease lies a continuum in which asymptomatic infection may progress to tuberculosis (TB) disease over an extended timeframe. The host response that must evolve as the infection progresses toward disease has not been defined. Equally unclear is the role of Mtb-intrinsic factors in modulating the host response and consequently, the kinetics of the progression of infection to disease. We have characterized a biomarker signature (PREDICT29) that can predict the risks for progression from infection. Clinical epidemiological study identified 2 classes of Mtb based on the capacity of the bacilli from index cases to be transmitted to cause infection in household contacts (HHC): Mtb-HT (high transmission) and Mtb-LT (low transmission). Chest x-ray of Mtb-HT IC displayed increased frequency of cavitary disease. Analysis of Mtb-HT and Mtb-LT in C3HeB/FeJ mice revealed remarkable differences among the 2 strains in i) the responses elicited in AM; ii) the immunopathological patterns, with lung necrotic lesions only apparent in Mtb-HT infected mice; iii) the T cell response during the chronic phase of infection; and iv) the expression of phthiocerol dimycocerosate (PDIM), an Mtb cell envelope lipid. These characteristics of Mtb-HT and Mtb-LT may thus link Mtb-intrinsic factors to differential regulation of the early innate immune response (the Mtb-AM interaction) that leads to the development of distinct adaptive immunity that in turn, governs the kinetics and frequency with which asymptomatic infection progresses to disease. PREDICT29 (segregates progressors vs nonprogressors), in conjunction with the ACS-COR signature (identifies individuals at a later phase of infection), enables the placement of subjects in our cohorts infected with Mtb-HT and Mtb-LT at the early phase of infection that are progressors or nonprogressors or late phase of infection. A combination of ex vivo cellular systems, singe-cell RNA-seq analysis, hi-dimensional mass cytometry, and Nanostring technology will be employed to characterize the immune response exhibited by these various subgroups. We propose to test the following hypothesis: i) Mtb-HT and Mtb-LT elicit differential AM response; ii) Disparate T cell and antibody response in HHC infected with Mtb-HT and Mtb-LT differentially regulate the immunopathology and progression to disease; iii) memory T cells play a role in regulating infection progression. Immunological analysis of these subgroups comprising Mtb-HT and Mtb-LT infected subjects in specific phase of infection, with a focus on the early Mtb-AM interaction, adaptive T cell and antibody response, will provide a large body of information that will shed light on the mechanisms that regulate infection and disease outcomes in the context of progressors and nonprogressors and Mtb- intrinsic factors.