With 8.9 million new cases and 1.7 million deaths per year tuberculosis is a leading AIDS-related global killer which has not been effectively controlled. The causative agent, Mycobacterium tuberculosis, proliferates within host macrophages where it modifies both its intracellular and local tissue environment resulting in caseous granulomas with incomplete bacterial sterilization. While infection by various mycobacterial species produces a cyclic AMP (cAMP) burst within macrophages that influences cell signaling, the underlying mechanism for the cAMP burst has remained unclear. We recently reported that among the 17 adenylate cyclase genes present in M. tuberculosis, at least one (Rv0386) is required for virulence. The bacterial Rv0386 adenylate cyclase facilitates delivery of bacterium-derived cAMP into the macrophage cytoplasm. Loss of Rv0386 and the intramacrophage cAMP it delivers, results in reductions of TNF-1 production via the PKA-CREB pathway, decreased immunopathology in animal tissues, and diminished bacterial survival. Recent unpublished data indicated that secretion of matrix metalloproteinases MMP-1 and MMP-9 from infected macrophages is induced by an Rv0386-cAMP dependent mechanism. We hypothesize that direct intoxication of host cells by bacterial-derived cAMP may enable M. tuberculosis to modify both its intracellular and tissue environment to facilitate its long-term survival. This application will address the hypothesis is that Rv0386-cAMP-dependent subversion of host cell signaling requires bacterial transporters that facilitate release of cAMP from the microbe (Aim 1). It will assess the role Rv0386-cAMP signaling on granuloma formation specifically focusing on the induction of MMP secretion by Rv0386-dependent mechanisms (Aim 2). Lastly, it will address the role of cAMP-dependent MMP expression in cavity formation using the novel rabbit cavitation model developed at JHU (Aim 3).
The bacteria causing TB enter human cells and subvert normal human cell signaling by secreting excess levels of the second-messenger, cyclic-AMP;we have observed that this process enables the microbe to elicit an excessive inflammatory response that harms the host and benefits the microbe. This study will identify the specific mechanisms and inflammatory processes that are subverted by bacterial cyclic-AMP secretion in order to identify targets in the host and the microbe that may be interrupted.
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