Latent tuberculosis infection: myths, models, and molecular mechanisms

Abstract

The aim of this review is to present the current state of knowledge on human latent tuberculosis infection (LTBI) based on clinical studies and observations, as well as experimental in vitro and animal models. Several key terms are defined, including "latency," "persistence," "dormancy," and "antibiotic tolerance." Dogmas prevalent in the field are critically examined based on available clinical and experimental data, including the long-held beliefs that infection is either latent or active, that LTBI represents a small population of nonreplicating, "dormant" bacilli, and that caseous granulomas are the haven for LTBI. The role of host factors, such as CD4(+) and CD8(+) T cells, T regulatory cells, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ), in controlling TB infection is discussed. We also highlight microbial regulatory and metabolic pathways implicated in bacillary growth restriction and antibiotic tolerance under various physiologically relevant conditions. Finally, we pose several clinically important questions, which remain unanswered and will serve to stimulate future research on LTBI.

FIG 1

Histological comparison of TB lesions in different experimental animals.

FIG 2

A complex feedback regulatory loop involved in the M. tuberculosis stringent response. PPK, polyphosphate kinase; PPX, exopolyphosphatase; Pi, inorganic phosphate; rac, M. tuberculosis Rel-activating complex, consisting of the ribosome, tRNA, and mRNA. (Courtesy of Harvey Rubin, University of Pennsylvania School of Medicine.)

FIG 3

Flowchart of a systems biology-based approach to studying latent TB infection and reactivation. Using an integrated, multidisciplinary approach, including the use of several novel animal models of LTBI in combination with transcriptional, proteomic, genetic, imaging, and computational techniques, researchers can begin to identify host cytokine networks responsible for immunological control of M. tuberculosis (Mtb) growth, as well as M. tuberculosis regulatory and metabolic pathways required for bacillary growth restriction and reactivation. Computational predictions of redundant host and M. tuberculosis molecular pathways required for LTBI and reactivation across experimental models can be tested directly by dual inhibition of host cytokine pathways and by generation of M. tuberculosis double knockouts. Finally, the biological relevance of the computational and experimental findings may be verified using plasma and peripheral blood mononuclear cell samples collected serially from latently infected persons before and after TB reactivation./