ABSTRACT - OVERALL Until recently, Tuberculosis (TB) has been viewed as a disease that progresses over several discrete stages, principally consisting of a period of infection followed by either active TB disease or a latent state with the potential for reactivation. Similarly, Mycobacterium tuberculosis (Mtb), the causative agent of TB, has been viewed as a relatively stable bacterium with little genomic diversity, predictable causes of antibiotic resistance, and phenotypic uniformity both during culture and within its infected host. However, recent findings, many spearheaded by the members of this application, have begun to discover unexpected heterogeneity in TB disease states, host responses, the genotypes and phenotypes of the bacteria, and among the apparently clonal infecting population of Mtb. The premise for this program is that the heterogenous outcomes of TB infections and treatments are determined by the interplay between heterogeneous host-bacteria transcriptional and metabolic programs. Host and bacteria may be pre-programmed phenotypically or genetically to progress from TB infection to TB disease; and to do so rapidly or slowly; and, with or without extensive inflammation and lung damage. Immune tolerance, evasion or subversion may be another result of these interactions, which could lead to worsening disease and adverse treatment outcomes including relapse. Drug tolerance or resistance is another result of these interactions that may have widespread effects on treatment responses. Although Mtb-host and Mtb-drug interactions would seem to be unrelated, we will also study the possibility that immune and drug tolerant Mtb share a number of transcriptional and metabolic programs; and thus, also share some of the same vulnerabilities that could provide therapeutic targets. Consisting of 4 Projects and 3 Cores, this program will be accomplished in the following Specific Aims: 1) To determine the effects of bacterial and host heterogeneity on the manifestations, progression and consequences of close exposure to TB in the household, and of active TB. Addressed in Project 1: Bacterial and Host Determinants of Progression, Manifestations and Consequences of TB. 2) To uncover the immunological mechanisms underlying the diverse clinical outcomes in hosts infected with high and low transmission strains of Mtb. Addressed in Project 2: Immune Determinants of the Course of Mtb infection and Disease. 3) To define the host immune pathways that induce drug tolerance and identify potential routes to therapeutic intervention. Addressed in Project 3: Minimizing in vivo Drug Tolerance Induction in TB. 4) To define bacterial factors that contribute to the heterogeneous expression of drug tolerance and characterize links with adverse treatment outcomes. Addressed in Project 4. Drug Tolerance, Bacterial Heterogeneity and Adverse TB Treatment Outcomes.

This project will identify common ways that M. tuberculosis bacteria avoids being killed by drugs that would normally work against them. It will also determine if this ability to avoid killing leads to relapse of disease after treatment. Identifying the shared mechanisms underlying these behaviors should make it possible to design new drugs that work better for treating TB and to develop new tests that can better guide therapy.