Bacterial and Host Heterogeneity in TB latency, persistence and progression

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.

Grant Number: 3U19AI162598-05S2
NIH Institute/Center: NIH
Principal Investigator: David Alland