LIFE CYCLE STAGES AND PATHOGENICITY OF M TUBERCULOSIS

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Mycobacterium tuberculosis has re-emerged over the last decade as an increasing health risk in inner cities and in immunocompromised individuals. The success of the pathogen is due in large part to its ability to infect and persist within the phagocytes of its host. Classical tuberculosis is the reactivation of a latent infection where the balance between the host and pathogen has apparently shifted in favor of the bacteria. This delicate interplay between Mycobacterium tuberculosis and its host is poorly understood yet it holds the key to the control of tuberculosis. The biology of the bacterium and its intracellular environment lie at the center of the transition from a dormant state to a fulminating infection. Although Mycobacterium does not show clear morphological differentiation during its life cycle we have found that its environment can markedly alter its pattern of protein synthesis, revealing distinctive sets of intracellular "stasis" and "growth" polypeptides. In this proposal we describe an integrated approach that will enable us to define the properties of the intramacrophage vacuole inhabited by M. tuberculosis and characterize the protein synthesis profiles of the intracellular "stasis" and "replicative" life cycle stages of the bacterium. This information will then be applied to understanding the biology of reactivation tuberculosis in a murine lung model. The development of the infection foci will be experimentally manipulated through the use of "knockout" mice and modulation of the cellular immune response.