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 Recent unpublished data indicated that secretion of matrix metalloproteinases MMP-1 and MMP-9 from infected macrophages is induced by an Rv0386-cAMP dependent mechanism.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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037856-12
Application #
8135503
Study Section
Special Emphasis Panel (ZRG1-AARR-C (04))
Program Officer
Lacourciere, Karen A
Project Start
1997-04-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
12
Fiscal Year
2011
Total Cost
$454,875
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rockwood, Neesha; Costa, Diego L; Amaral, Eduardo P et al. (2017) Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes. Front Immunol 8:542
Dey, Ruchi Jain; Dey, Bappaditya; Zheng, Yue et al. (2017) Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nat Chem Biol 13:210-217
Gupta, Shashank; Winglee, Kathryn; Gallo, Richard et al. (2017) Bacterial subversion of cAMP signalling inhibits cathelicidin expression, which is required for innate resistance to Mycobacterium tuberculosis. J Pathol 242:52-61
Manson, Abigail L; Cohen, Keira A; Abeel, Thomas et al. (2017) Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance. Nat Genet 49:395-402
Gupta, Shashank; Cheung, Laurene; Pokkali, Supriya et al. (2017) Suppressor Cell-Depleting Immunotherapy With Denileukin Diftitox is an Effective Host-Directed Therapy for Tuberculosis. J Infect Dis 215:1883-1887
Singh, Alok Kumar; Bishai, William R (2017) Partners in Crime: Phenolic Glycolipids and Macrophages. Trends Mol Med 23:981-983
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
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
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
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

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