Molecular mechanisms of cell growth in mycobacteria

Mycobacterium tuberculosis and Mycobacterium bovis are the causative agents of tuberculosis in humans and cattle respectively. A key virulence factor in the success of tuberculosis as a pathogen in mammalian hosts is the ability to form dormant cells which are capable of persisting within the host. This study will focus on proteins involved in the regulation of gene expression, as well as proteins involved in cell growth and division in order to elucidate the molecules and pathways involved in the execution of the dormancy phase.

Preliminary studies into genes regulating gene expression, as well as the division and final structure of cells, have revealed a number of genes which show a significant change in the appearance, replication and structure of mycobacteria in cell culture. Our aim is to use homologs of these genes in the non-toxic, rapidly growing Mycobacterium smegmatis, which is closely related to M. tuberculosis, to develop a greater understanding of the roles of these genes and the proteins they encode. We will achieve this through targeted overexpression and knockout mutants, with subsequent analysis of the visual changes in cell morphology, alongside assessment of the molecular changes in protein expression, interaction and localisation, as well as the impact of this overexpression on lipid profiles, which form an essential part of mycobacterial function.