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Translational regulation in the persistence and drug susceptibility of Mycobacterium tuberculosis

Objective

Mycobacterium tuberculosis causes human tuberculosis but can also persist for decades as an asymptomatic latent infection. The mechanisms underlying persistence are poorly understood, and the emergence of drug-resistant tuberculosis 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 to the search for improved treatments.
The number of copies of a protein produced by a cell is generally viewed as being determined by the number of mRNA transcripts, but recent findings suggest that ‘specialised ribosomes’ can modify proteome profiles by preferential translation of particular mRNA subsets, particularly in response to stress. mRNA molecules 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. I recently demonstrated that M. tuberculosis expresses an unexpected number of leaderless mRNA transcripts that lack the SD sequence. In Escherichia coli, only a few leaderless transcripts have been described and they are selectively translated by specialised ribosomes. I propose to test the hypothesis that differential translation of mRNA subsets contributes to M. tuberculosis persistence and drug susceptibility.
I will investigate the importance of selective translation of leaderless and SD mRNAs in the context of adaptation to stress and drug resistance in M. tuberculosis, using cutting-edge experimental techniques combined with bioinformatic analyses. The proposed project addresses the fundamental systems biology challenge of establishing quantitative correlations between transcriptome and proteome data, and beyond contributing to the rational design of novel treatments to cure tuberculosis, could help to re-shape classical paradigms of bacterial gene regulation.

Field of science

  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance
  • /medical and health sciences/clinical medicine/pneumology/tuberculosis
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics

Call for proposal

ERC-2014-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER
Address
Keppel Street
WC1E 7HT London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 495 625

Beneficiaries (1)

LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE ROYAL CHARTER
United Kingdom
EU contribution
€ 1 495 625
Address
Keppel Street
WC1E 7HT London
Activity type
Higher or Secondary Education Establishments