Grant: Master's Award: Canada Graduate Scholarships

The proposed research project aims to understand the bacteriological differences between the bacteria that causes tuberculosis (TB) in humans (Mycobacterium tuberculosis) and the closely-related bacteria that causes TB in cows (Mycobacterium Bovis). M. tuberculosis transmits efficiently between humans but is less virulent in most animal models; the converse is true for M. bovis. These different pathogenic profiles are not due to additional genes in M. bovis, but rather due to differential expression of genes that are shared by the two organisms. Specifically, the expression differences between these organisms result from mutations in the regulator of Sigma Factor K, RskA. Mutations in RskA of M. bovis explain the high level of expression of the antigenic proteins MPT83 and MPT70 and their activation is hypothesized to be responsible for the enhanced pathogenicity of M. bovis in animal models. To better understand the role of the SigK regulon in M. tuberculosis infection, we will screen mutants that we have engineered to look for partner genes required for SigK-regulated expression. By defining the regulatory system that controls expression of these highly antigenic proteins, we will also generate mutants of variable levels of expression that will be used in pathogenicity studies. Together, these studies will allow us to understand how mutations affecting SigK impact on the host-pathogen interaction. Previous work defining the genomic differences between M. tuberculosis and M. bovis has uncovered molecular targets that are already in use by clinical labs for routine diagnostic work. Through an understanding of the SigK regulon in M. bovis and in M. tuberculosis, we believe that transcriptional differences will enhance our fundamental understanding of how closely-related members of the M. tuberculosis complex differentially infect and cause disease in the host. Ultimately, this information will inform novel vaccine strategies to control TB.