Mycobacterium tuberculosis Dormancy: How to Fight a Hidden Danger

Abstract

Both latent and active TB infections are caused by a heterogeneous population of mycobacteria, which includes actively replicating and dormant bacilli in different proportions. Dormancy substantially affects M. tuberculosis drug tolerance and TB clinical management due to a significant decrease in the metabolic activity of bacilli, which leads to the complexity of both the diagnosis and the eradication of bacilli. Most diagnostic approaches to latent infection deal with a subpopulation of active M. tuberculosis, underestimating the contribution of dormant bacilli and leading to limited success in the fight against latent TB. Moreover, active TB appears not only as a primary form of infection but can also develop from latent TB, when resuscitation from dormancy is followed by bacterial multiplication, leading to disease progression. To win against latent infection, the identification of the Achilles’ heel of dormant M. tuberculosis is urgently needed. Regulatory mechanisms and metabolic adaptation to growth arrest should be studied using in vitro and in vivo models that adequately imitate latent TB infection in macroorganisms. Understanding the mechanisms underlying M. tuberculosis dormancy and resuscitation may provide clues to help control latent infection, reduce disease severity in patients, and prevent pathogen transmission in the population.

Drug-Tolerant Mycobacterium tuberculosis Adopt Different Survival Strategies in Alveolar Macrophages of Patients with Pulmonary Tuberculosis

“…Interestingly, both the regrowth and resumption of the pathogen in the alveolar macrophages of some patients were achieved without the use of any special resuscitationpromoting factors or other products of Mtb in a long-term ex vivo culture. Meanwhile, many substances were necessary for resuscitation of Mtb in the different in vitro dormancy models with a wide spectrum of stressful conditions in stationary phase [66][67][68][69] and from the sputum of patients with active TB disease [70], while the Mtb transition from a dormant, nonreplicating state to an actively dividing state was estimated by a standard colony-forming assay. We hypothesize that Mtb, as an intravacuolar pathogen in the viable host cells of TB patients [35], are likely to be able to monitor stressful environments, including exposure to anti-TB drugs, through the interaction of the Mtb phagosomes and human endocytic pathways, as we have established previously [35], and to quickly resume the growth in favorable conditions, especially in colonies with cording morphology, for some patients.…”

“…Taken together, these results strongly suggest that the modulation of the LAM content that was detected in both the pathogenic and non-pathogenic mycobacteria, is a well-coordinated, growth phase-and environmental-signal-regulated process likely affecting the cell wall integrity and unique acid-fast property of mycobacteria. Overall, while in vitro and in vivo animal models remain some of the main sources of knowledge about the mechanisms of Mtb survival under multiple stressful conditions (reviewed in [68,69]), they are unlikely to reflect the actual situation in human TB disease or the true interaction between the pathogen and host cells under the treatment of TB patients. Therefore, future studies of Mtb persistence, dormancy, and resumption as well as the identification of biomarkers characterizing these phenomena and the biological states and growth features of the pathogen in humans are very important.…”

Eradication of Drug-Tolerant Mycobacterium tuberculosis 2022: Where We Stand

“…Several studies have reported the presence of DD Mtb cells in the sputum produced by patients with active TB. These cells are not able to form colonies on standard glycerol-based solid media (7H10 agar plates and Löwenstein-Jensen slants) but can grow in liquid media supplemented with mycobacterial culture filtrates (CF) [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 61 , 62 ] or other substances, such as cyclic-AMP [ 17 ] and fatty acids [ 63 , 64 ]. The growth stimulatory effect of CF was ascribed to the five resuscitation-promoting factors (Rpfs) of Mtb, which have the ability to resuscitate non-culturable cells [ 12 , 65 ].…”

Mycobacterial Endocarditis, A Rare Form of Infective Endocarditis

“…This process can cause productive cough, enabling pathogen spread to different lung areas [11]. The bacterium may also remain dormant in a non-replicating granuloma state, leading to a latent form of M.tb [12] (Fig. 1).…”