Mycobacterium tuberculosis (Mtb) is a significant threat to both immunocompromised and immunocompetent populations. Mtb is an intracellular organism with an extremely complicated life cycle involving resistance to normal host defense mechanisms and subsequent development of a latent state. Similarly, the host response to Mtb infection is a complex series of immune events resulting in granulomatous inflammation to control Mtb proliferation with subsequent formation of granulomas that maintain Mtb in a latent state. The development of drug resistant Mtb strains has made the understanding of its pathogenesis a high priority in order to identify potential targets for antibiotics and immunomodulatory interventions. The recent sequencing of the Mtb genome has provided an exciting database for aiding in dissecting Mtb pathogenesis. Together with the application of microarray technology to in vivo infections, there is the potential for an analysis of genome wide expression during different stages of infection. We hypothesize that during the dynamic interactions between the host and the Mtb there is a series of changes in the environment that lead to differential expression of genes that enhance survival for both the host and the Mtb. We intend to use microarray analysis to determine the gene expression that occurs during a pulmonary infection with Mtb in the mouse. We will use arrays that contain all open reading frames of the Mtb genome as well as an array containing approximately 100 immunoresponsive murine genes. This will allow us to correlate changes in the host that result in changes in the organism. Finally, we will use an in vivo luciferase based technology to track Mtb infections and gene expression in real time. The development of this model will provide a high through put system for testing therapeutic interventions using fewer mice than standard assays as well as significantly enhance our ability to monitor specific Mtb gene expression in vivo.
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