"Regulation of the Mycobacterium tuberculosis DosR regulon during non-respiring conditions"
Prepared under the direction of: Martin I. Voskuil, Ph.D.
Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease that affects one-third of the world's population and results in the deaths of thousands of people each day. The DosR regulon is a set of genes that is strongly induced by blocking respiration via oxygen limitation, nitric oxide, or carbon monoxide, and mounting evidence suggests that these genes are important for latent human infection. Several aspects of this regulon and its induction are explored in this work, each relating to bacterial respiration.
First, differences in DosR regulon induction between various strains of Mycobacterium bovis bacille Calmette-Guérin (BCG), the vaccine strain for M. tuberculosis, are defined. These differences shed light on the existence of respiratory differences between these strains and M. tuberculosis as well as provide possible biomarkers to clinically distinguish between latent infection and vaccination. The remainder of the thesis addresses the regulon's induction by its two sensor kinases, DosT and DosS, with the goal of providing a greater understanding of signaling and induction of the regulon in order to aid in elucidating the conditions the bacillus encounters in infection. Further, it will also indicate what the function of the regulon as a whole may be - as the stimuli and timing of induction are better understood, the function of the genes themselves will become more apparent. The work on DosT and DosS illustrates why there are two sensors, how and when they function, and further elucidates the specifics of their induction signals. The final data chapter describes ongoing and proposed work on two proteins in the DosR regulon, Rv2007c and Rv1812, and their role in DosS sensing and electron transport.