Mycobacterium tuberculosis is the causative agent of human tuberculosis (TB), one of the humankind’s deadliest diseases. The World Health Organisation estimated that there were 10 million new cases of TB and 1.5 million TB deaths in 2020. Furthermore, it is estimated that one-quarter of the world’s population harbours the bacterium in the form of an asymptomatic infection referred to as latent TB. This reflects the complex life cycle of the bacteria that can involve prolonged periods of non-replicating persistence prior to the active disease process that is required for onward transmission. During this process, the bacteria overcomes numerous stresses presented by the immune system of the host. Still today, the mechanisms underlying persistence are poorly understood, and the emergence of drug-resistant bacteria makes the development of effective new treatments an urgent challenge. Understanding the ability of M. tuberculosis to switch between replicating and non-replicating states during infection and disease is central in the search for improved treatments.
Translation, the process by which the sequence of nucleotides in a gene directs the synthesis of proteins, is an intricate process involving many cellular components. The ribosome has been traditionally considered as a conserved nucleoprotein with the only role of mediating this process. Genes contain specific signals that optimise their interaction with ribosomes, known as leader sequences, these include the Shine-Dalgarno (SD) sequence required for canonical translation initiation in bacteria. There is recent evidence that suggests that ‘specialised ribosomes’, which are modified ribosomal particles, can modify the proteome profile by preferential translation of particular gene subsets, particularly in response to stress. M. tuberculosis differs from other important human pathogens in expressing a large number of leaderless genes, which do not have the SD sequence required for canonical translation initiation. In the model bacteria Escherichia coli, only a few leaderless genes have been described, and they are selectively translated by specialised ribosomes upon stress conditions. We have previously shown in M. tuberculosis that under conditions of nutrient starvation, the abundance of leaderless genes increases, suggesting that translation of leaderless genes may be an important component of the adaptive response of this pathogen.
The MtbTransReg project aims at understanding what is the role of selective translation of leaderless and SD genes in the context of adaptation to stress and drug resistance in M. tuberculosis. It is divided in three main objectives. The first objective aims at identifying differences in translation efficiencies during different growth conditions. The second objective is focused on determining what are the molecular mechanisms underlying differences in translational efficiencies. Finally, the third objective is devoted at establishing relationships between translational regulation and drug susceptibility in M. tuberculosis.
