Application of model systems to study adaptive responses of Mycobacterium tuberculosis during infection and disease

Tuberculosis (TB) claims more human lives than any other infectious organism. The lethal synergy between TB-HIV infection and the rapid emergence of drug resistant strains has created a global public health threat that requires urgent attention. Mycobacterium tuberculosis, the causative agent of TB is an exquisitely well-adapted human pathogen, displaying the ability to promptly remodel metabolism when encountering stressful environments during pathogenesis. A careful study of the mechanisms that enable this adaptation will enhance the understanding of key aspects related to the microbiology of TB disease. However, these efforts require microbiological model systems that mimic host conditions in the laboratory. Herein, we describe several in vitro model systems that generate non-replicating and differentially culturable mycobacteria. The changes that occur in the metabolism of M. tuberculosis in some of these models and how these relate to those reported for human TB disease are discussed. We describe mechanisms that tubercle bacteria use to resuscitate from these non-replicating conditions, together with phenotypic heterogeneity in terms of culturabiliy of M. tuberculosis in sputum. Transcriptional changes in M. tuberculosis that allow for adaptation of the organism to the lung environment are also summarized. Finally, given the emerging importance of the microbiome in various infectious diseases, we provide a description of how the lung and gut microbiome affect susceptibility to TB infection and response to treatment. Consideration of these collective aspects will enhance the understanding of basic metabolism, physiology, drug tolerance and persistence in M. tuberculosis to enable development of new therapeutic interventions.