In vivo regulation of M. tuberculosis cell wall lipids

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This is a revised abstract of an application of a proposal being considered for funding through the American Recovery and Reinvestment Act. The goal of this project is to characterize the role of an M. tuberculosis operon called mcel associated with latent TB infection. This project is based on a new hypothesis that M. tuberculosis needs to readapt to the constantly changing environment of the host granulomatous lesion in which the bacilli reside. We have evidence that this intra-granuloma adaptation is mediated by M. tuberculosis remodeling its cell envelope in response to signals produced by apoptotic cells. We propose that this remodeling is regulated by the mcel operon of M. tuberculosis. Previous studies have shown that an M. tuberculosis strain disrupted in the mcel operon becomes hypervirulent in mice and is unable to elaborate organized granulomas in mouse lungs. An M. tuberculosis strain disrupted in the negative regulator of this operon called mcel R is also hypervirulent in mice. With the former mutant, mouse dies because of uncontrolled bacterial proliferation while with the latter, the mouse dies because of uncontrolled inflammation. Thus, these two extreme granuloma-related clinical outcomes in immunocompetent mice are induced simply by affecting the expression of the mcel operon genes. This suggests that this operon plays a homeostatic role in response to granuloma formation. M. tuberculosis contains 3 other members of this mce operon called mce2, 3, and 4. The mce3 and mce4 mutants have been tested in mice, and they show a phenotype distinct from that of the mcel operon mutant--they are attenuated in mice. Thus, the functions of the 4 mce operons may vary, but they may also be related. The specific aim of this project for the revised 2-year project is to characterize the function of the mcel operon as a possible lipid transport system or regulator and how this may contribute to remodeling M. tuberculosis cell envelope in response to granuloma cell turnover for the bacillus to establish infection. The previous additional aim to characterize the relationship of the mcel operon to mce2, 3, and 4 operons will be done under a support mechanism to which we plan to apply in Yr 2 of this project. We believe this characterization of the relationship between M. tuberculosis and granulomas may contribute to our understanding of the mechanism of persistence of M. tuberculosis that could lead to new tests to differentiate active TB from latent TB infection.