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Aspects of the pathogenesis, immunity and treatment of Buruli ulcer

Bieri, Raphael. Aspects of the pathogenesis, immunity and treatment of Buruli ulcer. 2015, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12174

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Abstract

Buruli ulcer (BU) is a neglected tropical disease of the skin and subcutaneous tissue caused by infection with Mycobacterium ulcerans. The disease has been reported from over 30 countries worldwide with the highest prevalence in rural areas of West African countries. Clinically, M. ulcerans disease presents in different forms, ranging from small non-ulcerative nodules to large ulcers. The pathology of BU is largely attributable to the production of mycolactone, a lipid-like macrolide exotoxin with cytotoxic and immunosuppressive characteristics. Although mycolactone-induced cytotoxicity and tissue necrosis are the key elements of BU pathogenesis, the molecular mechanisms underlying these processes remained to be elucidated.
Within the framework of this PhD thesis, we could show that mycolactone binds to the 12-kDa FK506-binding protein and acts as a potent inhibitor of both mTORC1 and mTORC2. Inhibition of mTORC2 results in inactivation of Akt and dephosphorylation and activation of the Akt-targeted transcription factor FoxO3. Subsequent up-regulation of the FoxO3 target gene Bim, a pro-apoptotic member of the Bcl-2 protein family, was observed both in vitro and in human BU lesions. Moreover, Bim knockout mice were able to contain M. ulcerans infection and did not develop necrotic lesions with large clusters of extracellular bacilli typical for BU, highlighting the pivotal role of Bim-promoted apoptosis for BU pathogenesis.
In addition, we aimed at characterizing the nature of immune defense mechanisms conferring protection against BU. Specifically, we focused on the role of interferon-γ and of cellular immune effector mechanisms during the early intracellular stage of M. ulcerans infection. We could show that interferon-γ is critical for early host immunity against M. ulcerans, since mice lacking this cytokine showed a faster increase in bacterial burden and an accelerated pathogenesis, indicative of a reduced capacity to kill the bacilli during the early intracellular stage of the infection.
Finally, we evaluated the activity of the new tuberculosis drug candidate Q203 against M. ulcerans using the BU mouse foot pad infection model. In this project, we were able to demonstrate that Q203 has a higher activity against M. ulcerans than rifampicin, and might therefore be suited to replace rifampicin as the first line therapeutic option in the future.
Advisors:Münz, Christian and Pluschke, Gerd
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Molecular Immunology (Pluschke)
UniBasel Contributors:Bieri, Raphael and Pluschke, Gerd
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12174
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (X, 164 Seiten)
Language:English
Identification Number:
Last Modified:29 Jun 2018 07:25
Deposited On:15 Jun 2017 09:40

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