M. bovis as a potentially more virulent MDR pathogen

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DESCRIPTION (PROVIDED BY APPLICANT): Virulence may be defined as the ability of a microorganism to survive host defenses and cause disease. There is no reason to believe that multi-drug resistant (MDR) strains of Mycobacterium tuberculosis are more virulent than drug sensitive (DS) strains There is evidence, on the other hand, that M. bovis is much more virulent than M. tuberculosis as a species. Therefore, if M. bovis were engineered to be MDR, it could pose a more serious threat to public health than MDRM. tuberculosis. The proposed research will use the superior virulence for mice of the Ravenel strain of M. bovis over M tuberculosis H37Rv to determine whether superior virulence, as manifest by ability to induce faster development of lung pathology and cause earlier death, is associated with the ability to induce a higher level of expression of Th1 immunity in the lung. This will be investigated by measuring levels of expression of genes for Th1 cytokines, proinflammatory cytokines and chemokines in the lungs. Elispot and flow cytometry will be used to enumerate total numbers of IFN-?, producing, pathogen-specific CD4 and CD8 T cells in the lungs. The possibility that superior virulence of M. bovis is also associated with higher levels of bacterial gene expression will be investigated, keeping in mind that M. bovis Ravenel and M. tuberculosis cause the same level of stationary lung infection. Real-time RT-PCR will be used to measure levels of pathogen gene expression in terms of mRNA copy number per lung and per CFU. Genes within the RD1 region of the M. tuberculosis and M. bovis chromosome, including esat6 and cfp-10, will receive attention. The virulence of a number of M. bovis and M. tuberculosis strains will be compared.