The role of small regulatory RNAs in Mycobacterium tuberculosis pathogenesis

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Mycobacterium tuberculosis, remains a major threat to global health. It is responsible for more deaths than any other bacterium and claims around 1.5 million lives every year in a deadly synergy with Human Immunodeficiency Virus (HIV), leaving ten million children orphaned by this disease. Rational design of drugs and vaccines to combat tuberculosis is currently hampered by limitations in basic understanding of the biology of the bacterium. M. tuberculosis persists in the human host as multiple subpopulations, an adaptation that requires significant and appropriate changes in gene expression. Gene expression is a multi-step process, but research in M. tuberculosis has until recently focused on only the first step, which is largely regulated by protein factors. However, it has become evident that novel and quite different non-protein regulators, the so-called small RNAs (sRNAs), play a major role in stress responses in all bacteria. In the case of disease causing bacteria (i.e. pathogens), these sRNAs play a crucial role in the adaptation to hostile host environments. sRNAs are able to modify the final outcome of gene expression after the initial step has taken place, by either promoting or inhibiting the next step in gene expression, that is, the production of bacterial proteins. These proteins include the building blocks of the cell as well as various effector molecules such as regulators and factors that are secreted in order to interfere with the host's defence against the invading pathogen. This project aims at investigating selected M. tuberculosis sRNAs that are highly expressed during infection and therefore might be of importance in host adaptation and development of the disease (pathogenesis). By artificially manipulating the levels of individual sRNAs we will be able to detect which genes and molecules may be affected by these regulators and hence what cellular mechanisms are involved. However, we will not only be able to determine what role the sRNAs play in pathogenesis. This project will also have broader implications in elucidating basic molecular mechanisms such as regulation of M. tuberculosis gene expression and metabolism, which will eventually provide us with a better understanding of the bacterium, and lead to the development of novel intervention strategies for tuberculosis.