Pathogen and host predictors of M. tuberculosis transmission

About This Grant

PROJECT SUMMARY Common ways to measure M. tuberculosis transmission are via acquisition of Th1-skewed T-cell immunity (e.g., interferon gamma release assays; IGRA) or new TB cases. However, these measurements may oversimplify and, in some cases, entirely miss M. tuberculosis transmission. For example, a substantial minority of highly-exposed individuals have T-cell responses to M. tuberculosis antigens that are not Th1- based. In addition, subclinical or asymptomatic TB is common, but often not captured clinically. Different strains of M. tuberculosis may have evolved different solutions to optimize transmission, which may associate with distinct phenotypes. In addition, as M. tuberculosis encounters hosts with different genetic backgrounds, immune status, age, and sex, the manifestations of infection outcomes may vary, due to both bacterial and host factors. We hypothesize that M. tuberculosis transmission outcomes are affected by both bacterial and human host (contact and index case) factors. We will test our hypothesis in the well-established RePORT- Brazil cohort study of TB cases and their close contacts. There were 1,188 TB cases and 1,930 contacts enrolled in Phase 1 (2015-2021), and ~1,000 TB cases and ~2,000 contacts will be enrolled in Phase 2 (2022- 2026). We will identify M. tuberculosis bacterial genetic and phenotypic features associated with M. tuberculosis transmission outcomes, including M. tuberculosis infection, subclinical TB, and clinical TB disease through bacterial association studies and mechanistic evaluation. We will also define M. tuberculosis transmission outcomes using multi-parameter profiling of human cellular immune responses in close contacts. Clinical and epidemiologic characteristics of the close contacts and their index TB cases will also be addressed, in prediction models of M. tuberculosis transmission that also incorporate M. tuberculosis genetic and host immune factors. Findings from this study could guide the development of targeted interventions, such as diagnostics for detecting highly transmissible M. tuberculosis strains, and host-directed therapies aimed at modulating immune responses to reduce transmission risk. The results will also provide insights for optimizing public health strategies, including contact tracing and targeted preventive therapy, specifically tailored to high- transmission settings.