Towards understanding latent tuberculosis Although mortality rates from tuberculosis (TB) have fallen, still over 8.8 million people are infected worldwide and over 1.4 million succumbed to the disease last year. Understanding how Mycobacterium tuberculosis is capable of switching to dormancy is vital if we wish to eradicate the latent TB cases. Health © Thinkstock M. tuberculosis, the causative agent of TB, has the unique feature of switching to dormancy to evade host immune attack. Dormant bacilli, however, are difficult to detect and are also refractory to standard treatments. Immune responses against mycobacterial lipid antigens represent an important mechanism of host defense. M. tuberculosis is believed to change its lipid metabolism and composition to evade clearance. Understanding how changes in lipid metabolism bring about the establishment of latent infection was the subject of the EU-funded ‘Latent tuberculosis: New tools for the detection and clearance of dormant Mycobacterium tuberculosis’ (Stoplatent-TB) project. The plan was to generate tools for understanding the bacterial mechanisms that lead to the metabolic stage of tuberculosis during dormancy. For this purpose, project partners used various metabolic models including hypoxia or starvation, as well as guinea pigs as a more adequate animal model of latent infection. The growth dependence of M. tuberculosis on lipids was also tested on a recently described adipocyte-based ex vivo model and other cells that do not produce lipids. These models could also serve to assay various therapeutic regimens in the future. In order to estimate the metabolic activity of the bacilli, the transcriptomic profile of M. tuberculosis under stress was measured by the novel approach of RNA sequencing. Additionally, scanning electron microscopy analysis revealed that the metabolic changes of bacilli under environmental conditions enriched in lipids had an impact on the phenotypic appearance of the bacteria. An important part of the Stoplatent-TB study was the testing of drug combinations able to kill aerobic, replicating bacteria populations, as well as hypoxic, non-replicating bacilli. Drug susceptibility of M. tuberculosis varied depending on the growth stage of the organism, and novel drugs showed more activity against dormant M. tuberculosis. The findings from Stoplatent-TB work on the mechanisms underlying the establishment of latency have important implications for the development of new control strategies. Importantly, they could potentially provide the basis for the design of better TB vaccines.
