Tuberculosis (TB) is a persistent lung infection that has plagued mankind for centuries and ranks as one of the most serious threats to world health today. The 2-3 million deaths attributed yearly to the disease, as well as the emergence of strains resistant to all of the available chemotherapeutic agents, urgently call for the development of new therapies to treat TB. For years, the identification of new drug targets has been hampered by the intractability of the bacillus to genetic analysis. Now with the advent of powerful genetic tools, combined with well-established mouse infection models, we have isolated novel M. tuberculosis mutants with lesions in individual genes that are required for normal growth during acute infection. Our initial results have led us to the hypothesis that M. tuberculosis influences host- pathogen contacts by utilizing the MmpL family of transporters to secrete biologically active lipids to the surface of the mycobacterial cell and ultimately into infected host cells. The studies proposed here give us the opportunity to test this model and thus understand the molecular details host- pathogen interactions critical during this stage of M.tuberculosis infection. Specifically, we will study a subset of Mmpls that are required for disease and identify the host-pathogen interactions mediated by these virulence molecules. We will determine the mechanism of transport of the cell wall lipid phthiocerol dimycocerosate (PDIM) by MmpL7 and seek to understand why this molecule is important for lung specificity of M. tuberculosis. Furthermore, we will identify the molecules transported by the other MmpL proteins identified by our genetic screens and determine their role in pathogenesis. Finally, we will determine if these molecules serve distinct roles in modifying the host for the benefit of the bacterium. Because members of the MmpL family of transporters are highly homologous to one another and to MmpL proteins of other mycobacterial pathogens, understanding the common mechanisms of their function may lead to the development of inhibitors that could be useful for treating a broad range of infectious diseases. The results from these studies will direct our long-term plans to understand the role secreted lipids play in the struggle between M. tuberculosis and the host. Ultimately, by understanding tuberculosis pathogenesis at the molecular level, we hope to aid in the discovery of new therapies to combat and eradicate this persistent infection.
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