Tuberculosis is an extremely successful pathogen with a penetrance of its host population, mankind, that is estimated by WHO to be close to 1/3 of the population of the planet. In areas of high endemnicity for HIV infection, such as SubSaharan Africa, tuberculosis is invariably the first infection to emerge as immunocompetence wanes. Tuberculosis is a serious additional burden to populations already suffering poverty, malnutrition and other infectious diseases. At the head of this bacterium's success lies its capacity to infect and persist within the macrophages of its host. As the macrophage is normally regarded as key in controlling all microbial invaders the success of Mycobacterium tuberculosis in subverting the antibacterial armory of the phagocyte is both intriguing and of concern. In this current application we propose to characterize the physiology of the intracellular environment in which M. tuberculosis resides and to examine the major carbon sources accessed by the microbe. The revised specific aims of this proposal are as follows: 1. Determining the physiology of the M. tuberculosis-containing phagosome. Exploiting novel assays developed in the laboratory, we will measure a range of physiological parameters in the M. tuberculosiscontaining phagosome. These parameters are key to bacterial survival and include proteolytic, ipolytic and b - galactosidase activities, as well as oxidative and nitrosative stress, 2. Establishing a link between phagosomal degradation and bacterial nutrition. Preliminary data indicate that M. tuberculosis resides in a compartment accessible to riacylglycerides and rich in lipase activity. This lipase will generate free fatty acids and glycerol, and release cholesterol from LDL, all excellent carbon sources for M. tuberculosis. We propose determining how the bacterium's metabolism is realigned to access these carbon sources.
Mycobacterium tuberculosis remains one of the greatest infectious disease killers of both the immunocompetent and the immunocompromised. Its success hinges on its capacity to infect and persist within the phagocytes of its host. This proposal employs novel and unique assays developed by this laboratory to elucidate how the bacteria survive within these immune-effector cells. The data generated will support our ongoing drug discovery program.
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