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 Recent unpublished data indicated that secretion of matrix metalloproteinases MMP-1 and MMP-9 from infected macrophages is induced by an Rv0386-cAMP dependent mechanism.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.
|Rogers, Zoe; Hiruy, Hiwot; Pasipanodya, Jotam G et al. (2016) The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism. EBioMedicine 11:118-126|
|Winglee, Kathryn; Manson McGuire, Abigail; Maiga, Mamoudou et al. (2016) Whole Genome Sequencing of Mycobacterium africanum Strains from Mali Provides Insights into the Mechanisms of Geographic Restriction. PLoS Negl Trop Dis 10:e0004332|
|Ahidjo, Bintou A; Maiga, Mariama C; Ihms, Elizabeth A et al. (2016) The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis. JCI Insight 1:e86017|
|Kubler, Andre; Larsson, Christer; Luna, Brian et al. (2016) Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis. J Infect Dis 213:618-27|
|Maiga, Mamoudou; Cohen, Keira; Baya, Bocar et al. (2016) Stool microbiome reveals diverse bacterial ureases as confounders of oral urea breath testing for Helicobacter pylori and Mycobacterium tuberculosis in Bamako, Mali. J Breath Res 10:036012|
|KÃ¼bler, AndrÃ©; Luna, Brian; Larsson, Christer et al. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 235:431-44|
|Sullivan, Zuri A; Wong, Emily B; Ndung'u, Thumbi et al. (2015) Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV. EBioMedicine 2:334-340|
|Gupta, Shashank; Tyagi, Sandeep; Bishai, William R (2015) Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother 59:673-6|
|Dey, Bappaditya; Dey, Ruchi Jain; Cheung, Laurene S et al. (2015) A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat Med 21:401-6|
|Maiga, Mariama C; Ahidjo, Bintou Ahmadou; Maiga, Mamoudou et al. (2015) Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother 59:7888-90|
Showing the most recent 10 out of 90 publications