In Vitro Model of Hypoxically Induced Nonreplicating Persistence of Mycobacterium tuberculosis

Abstract

Great progress has been made in the latter half of the twentieth century in the understanding of the immunology of tuberculosis and of strategies for chemotherapeutic management of this disease. Indeed, given the evidence that the dominant, and perhaps sole, ecologic niche of Mycobacterium tuberculosis is the infected human host, it seemed reasonable to hope that the disease could not only be controlled, but eradicated by the end of this century (1). These hopes are dashed by the periodic resurgence of tuberculosis in various populations. Undoubtedly socioeconomic factors have played a major role in the failure to eradicate this disease, but another, neglected, factor is the apparent ability of the tubercle bacillus to remain in a relatively quiescent state in the host, neither replicating and causing progression of disease, nor dying off and disappearing from the host's tissues, in spite of apparently adequate immune responses and aggressive chemotherapy.

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

“…Aerobic bacteria were grown in agitation in Dubos Tween-albumin broth (Difco, Detroit, MI) and collected at the midlog phase, that is, OD 600 of 0.4. D-Mtb was generated as previously described (21)(22)(23). Briefly, hypoxic bacteria were grown by stirring (120 rpm) in sealed glass tubes containing Dubos Tween-albumin broth and incubated for 25 d at 37˚C.…”

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

“…Low oxygen tension (hypoxia) is one of the leading factors frequently associated with the establishment and maintenance of latent TB [Wayne and Sohaskey, 2001], which presumably forces the pathogen to adopt a non-replicating but viable state in an anaerobic environment. The initial response to hypoxia of MTB includes the altered expression of about 100 genes, including the DosR regulon.…”

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

“…In vitro, tuberculoid mycobacteria can go into a dormant state [22], while a non-tuberculous mycobacterium like Mycobacterium smegmatis cannot [23]. The dormant state of M. tuberculosis closely resembles the M. bovis BCG dormant state, and both are biochemically and morphologically distinct from their respective growing states [23], and it is thought that that holds for M. bovis wild type as well.…”