Nonreplicating Persistence ofMycobacteriumTuberculosis

Abstract

There is ample clinical evidence, as well as evidence from animal experiments, that Mycobacterium tuberculosis can persist in tissues for months to decades without replicating, yet with the ability to resume growth and activate disease. Our knowledge of both macrophage physiology and the nature of tuberculous lesions in man and animals suggests that hypoxia is a major factor in inducing nonreplicating persistence (NRP) of tubercle bacilli. In vitro models reinforce this conclusion and provide insights into mechanisms that make NRP possible. There is evidence from in vitro models that the strategies employed by the bacilli to permit hypoxic NRP include restriction of biosynthetic activity to conserve energy, induction of alternative energy pathways, and stabilization of essential cell components to lessen the need for repair or replacement.

Complex pattern of Mycobacterium marinum gene expression during long-term granulomatous infection

“…Because the granuloma environment has been proposed to be of low oxygen tension (4,20) the M. marinum gap fusions were subjected to hypoxic growth conditions. No activation was observed in log-phase bacteria incubated at 0.1%, 1%, or 4% oxygen for 24 and 48 h. Similarly, none of the gap fusions were induced in stationary phase.…”

“…Alternately, the bacteria could be replicatively, transcriptionally, and metabolically active but kept in check by a dynamic equilibrium with the host immune system. Data from various human and animal models and in vitro studies of M. tuberculosis can be interpreted to support the existence of both states (3,4). A second key question is how a persistent bacterial infection is sustained indefinitely in the granuloma in the face of a robust host immune response.…”

Dormancy Associated Translation Inhibitor (DATIN/Rv0079) of Mycobacterium tuberculosis interacts with TLR2 and induces proinflammatory cytokine expression

“…Understanding the latent or dormant form of M. tuberculosis has been a tough endeavour because no significant animal models are available and the in vitro models are not quite successful or remain impractical. Further, the micro-environment of the granuloma, where the dormant M. tuberculosis lodges, is impermeable to the present day anti-TB drugs or there is less effect of antibiotics on dormant tubercle bacilli due to their non-replicating state [34]. Given this, the fundamental challenge in the control of tuberculosis could be due to the frustrating lack of state of art concerning molecular mechanisms triggering the onset of latency, the maintenance of the latent state and the reactivation of dormant bacilli.…”

Transcription factors Rv0081 and Rv3334 connect the early and the enduring hypoxic response of Mycobacterium tuberculosis

“…They are slowly replicating sub-populations that arise stochastically, presumably in response to the host microenvironment conditions. As such they are unresponsive to currently available antibiotics that typically target metabolically active cells [9–12], and these persisters are also thought to be responsible for disease relapse following chemotherapy [5,10,13,14]. …”

“…Larry Wayne and co-workers were the first to develop an in vitro model to mimic the hypoxic environment of the human granuloma [12,20,21]. In the Wayne model, a sealed, standing culture is incubated over an extended period while the bacteria deplete the available oxygen.…”