Mycobacterium tuberculosis, the causative agent of tuberculosis is responsible for more deaths world wide than any other pathogenic bacterium. Although most prevalent in developing countries, tuberculosis is become increasingly more widespread also in the industrialized world because of the emergence of (multi) drug resistant strains. In the proposed project we intend to identify mycobacterial proteins that could be used for the development of anti-mycobacterial compounds.
When people get exposed to bacteria that may cause disease, several different cells in the body become active to clean up these micro organisms that may cause disease by internalizing the bacilli and digest them. The cells that perform this `eating` function are called macrophages.
One important disease-causing microbe is Mycobacterium tuberculosis. These bacteria are inhaled through the airways into the lungs, after which macrophages will start to `eat` these bacteria. However, in contrast to what happens with many other bacilli, Mycobacterium tuberculosis is not digested, but survives within the belly of these macrophages, small sacs that are called phagosomes. Whereas these phagosomes normally fuse with other sacs (so-called lysosomes) that are full of degradative enzymes, mycobacteria actively block such fusion. Inside these phagosomes, the mycobacteria not only survive but also continue to grow and divide. The mechanisms that result in the survival of mycobacteria within macrophages are beginning to become understood. The mycobacteria induce the formation of a coat around the phagosome, preventing its fusion with lysosomes, pretty similar to building a firewall
The aim of the project is to characterize the proteins made by Mycobacterium tuberculosis that are responsible for building this firewall. These proteins may well be responsible for allowing Mycobacterium tuberculosis to survive within the macrophages, and as a result cause disease in infected individuals.
Most anti-tuberculosis drugs used today are intended to stop Mycobacterium tuberculosis growth. Instead, the strategy proposed here will lead to the identification of mechanisms that are involved in mycobacterial survival inside host cells, a crucial reservoir for Mycobacterium tuberculosis. Characterization of mycobacterial genes involved in intracellular survival may not only lead to the development of a novel class of antibiotics but also to the generation of an effective vaccine that would prevent the establishment of intracellular mycobacterial infections.