It is estimated that one third of the human population are latently infected with Mycobacterium tuberculosis, constituting a major reservoir of that mycobacteria.
The clinical definition of latency is clear, but the bacterial biology underlying this clinical situation remains poorly understood. Dormant tubercle bacilli are difficult to detect and are also refractory to standard treatments, preventing their clearance from infected tissues.
While dormant, the tubercle bacilli are considered to be under non-replicating (NR) stage. In such a condition,bacilli are not only difficult to be detected but also refractory to the standard treatments avoiding their clearance from the infected tissues. The proposal has been built on the basis of providing tools to understand the bacterial mechanisms that lead to metabolic stage of M. tuberculosis during dormancy as the basis of sorting out the detection and treatment of latent infection.
The main aim of this project is to analyze the basic activity of M. tuberculosis during dormancy, and the changes in that activity with drug treatment. We intend to develop tools to improve the detection and treatment of latent infection.
Several models of analysis will be studied to characterize the dormant tubercle bacilli. Those models are ranging from in vitro conditions, such as hypoxia or starvation, to in vivo analysis, such as the animal model. We propose to study previously tested models, and also checking some other newly described, such as the recently described adipocytes ex vivo model, the new developments of the classical model of hypoxia, and the use of the new animal model of latent infection. A set of drug combinations will be applied to determine their capability of clearance of the bacterial load. Due to its central role in the bacterial metabolism and growth, we will analyze the non-replicating stage of the M. tuberculosis bacilli by determining the pre-rRNA synthesis.
That knowledge may lead to the development of novel strategies targeted at the control of the latent infection.
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