INTEGRATION AND EXCISION OF PROPHAGES IN TUBERCULOSIS

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DESCRIPTION (Adapted from the Applicant's Abstract): Mycobacterium tuberculosis infections result in more deaths than any other single infectious agent. Over past ten years, substantial advances have been made in methods for the genetic dissection of the mycobacteria and the recent description of the complete genome sequence will expedite the discovery of new drugs, better vaccines and more rapid diagnostic methods. however, the molecular basis of M. tuberculosis pathogenesis, the mechanism of drug resistance, the central metabolic processes and the relationship of M. tuberculosis with its host, remain poorly understood. Bacteriophages play central roles in the biology of their hosts. Not only do they mediate genetic exchange among bacterial strains but they also are closely associated with determinants of bacterial virulence. For example, they frequently encode toxins or other factors that influence the pathogenic properties of the bacterial host. Mycobacterial phage studies have also provided numerous insights into the biology of M. tuberculosis and novel tools for its analysis. The genome of M. tuberculosis contains two prophage-like elements phiRv1 and phiRv2. However, these are not typical prophages in that they are both rather small-less than 10 kb in length-and do not contain a full complement of the genes needed for viral propagation. Nevertheless, they both appear to have intact recombination machineries, one that is related to the integrase system of mycobacteriophage L5, and one that contains a novel resolvase-like recombinase. Thus, while these prophages may not alone have the potential to generate infectious viral particles, they are probably mobile and may move in and out of the genome. In this study, the PI will investigate the prophage-like elements of M. tuberculoses to determine whether they have functional recombination systems; whether they act as Genetic Transfer Agents; and whether they play a role in virulence of M. tuberculosis.