: Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe persistent skin infection which has been recently designated an emerging infection in West Africa. The disease has a unique pathology. Despite extensive tissue damage and the presence of a heavy bacterial load, there is little acute inflammatory response to the organism. A single Buruli ulcer may cover 15 percent of a person's body surface; the only cure is surgery and skin grafting. A polyketide-derived macrolide toxin designated mycolactone has been identified in M ulcerans. Macrolides are produced as secondary metabolites by soil bacteria and fungi. They have enormous pharmaceutical value as cytostatins, immunosuppressants, antifungal agents, antihelminthic agents and antibiotics. Mycolactone is the first macrolide identified from a pathogen. Evidence suggests that mycolactone is responsible for most of the pathology in Buruli ulcer. Mycolactone-mediated phenotypes include cell cycle arrest, immunosuppression and death via apoptosis. Neither the genetics of mycolactone synthesis nor its mechanism of action are known. The goals of this proposal are: 1) to clone and sequence genes for mycolactone biosynthesis, 2) to construct mutants defective in mycolactone production, and 3) to begin characterizing events in the cellular pathways involved in mycolactone mediated cell death and immunosuppression using micro-array gene-expression technology. Results from these studies should have a significant impact on the treatment and prevention of Buruli ulcer as well as provide insight into potential role of polyketides in other mycobacterial diseases such as tuberculosis. In addition, this work may provide useful insight into macrolide cell biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049418-05
Application #
6861121
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Sizemore, Christine F
Project Start
2001-03-15
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2008-02-29
Support Year
5
Fiscal Year
2005
Total Cost
$286,000
Indirect Cost
Name
University of Tennessee Knoxville
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996
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Coutanceau, Emmanuelle; Decalf, Jeremie; Martino, Angelo et al. (2007) Selective suppression of dendritic cell functions by Mycobacterium ulcerans toxin mycolactone. J Exp Med 204:1395-403
Coutanceau, Emmanuelle; Marsollier, Laurent; Brosch, Roland et al. (2005) Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin. Cell Microbiol 7:1187-96
Marsollier, Laurent; Aubry, Jacques; Coutanceau, Emmanuelle et al. (2005) Colonization of the salivary glands of Naucoris cimicoides by Mycobacterium ulcerans requires host plasmatocytes and a macrolide toxin, mycolactone. Cell Microbiol 7:935-43
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Stinear, Timothy P; Mve-Obiang, Armand; Small, Pamela L C et al. (2004) Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans. Proc Natl Acad Sci U S A 101:1345-9