Host–Pathogen Interactions Influencing Mycobacterium tuberculosis Persistence and Drug Tolerance

Abstract

Mycobacterium tuberculosis (Mtb) infection stimulates host immune responses that limit bacterial replication. During pathogenesis, the bacterium must sense and adapt to a variety of stressful environments including nutrient limitation, hypoxia, and acidification of the environment. These cues can drive the bacterium to establish a state of non-replicating persistence (NRP). NRP bacteria are tolerant to antibiotics and are thought to play a role in the months long course of tuberculosis (TB) therapy. Therefore, understanding the molecular mechanisms of Mtb establishment and maintenance of NRP will provide key insights into Mtb pathogenesis and present new drug targets that may shorten the course of TB therapy. In this chapter, we will examine host–pathogen dynamics that are associated with Mtb persistence and drug tolerance, including the use of in vitro and in vivo models to study Mtb persistence. Specific in vitro models of NRP will be examined, with a focus on nutrient starvation, hypoxia and acidic pH as host-relevant environments that promote NRP. Therapeutic strategies to control Mtb persistence will be also examined, with a focus on newly discovered compounds that target redox homeostasis, cell envelope integrity, respiration and ATP homeostasis, and the DosRST signaling pathway.