Epidemiology of Mycobacterium ulcerans disease in the Bankim Health Distrit of Cameroon and monitoring of the healing process of Buruli Ulcer lesions

Buruli ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans which, if untreated, can lead to extensive tissue destruction and ulceration. The disease has been reported from over 30 countries with the highest prevalence in West Africa. Generally it is assumed that M. ulcerans is acquired from environmental sources, but BU is considered a "mysterious disease" because the natural reservoir and the mode of transmission are still not identified. Clinically BU presents with a spectrum of forms ranging from non-ulcerative lesions to large ulcers. The gold standard for diagnosing BU is IS2404 qPCR, which is a sophisticated technology not applicable in the field, where BU is often diagnosed on the basis of clinical signs and symptoms only. Direct microscopic smear examination after Ziehl-Neelsen staining, which has a low sensitivity, is the only point-of-care laboratory diagnostic method currently available. Since 2004, the WHO recommends to treat BU with a combination of streptomycin and rifampicin daily for 8 weeks. While this specific treatment is highly effective in killing the bacteria, healing of large ulcers may require long periods of time. The Bankim Health District (HD) in the Mapé dam basin of Cameroon has been recently identified as BU endemic area and a new BU field research site was established by us in 2010. Within the framework of this thesis, we have contributed to strengthening of the local BU treatment and research site by the implementation of a surveillance and documentation system to promote a continuous case detection and follow up of patients, to investigate the pathway of transmission and to perform a comprehensive spatio-temporal distribution analysis of BU in the area. Local clinical and microscopic diagnosis was re-confirmed by qPCR, bacterial culture and histopathology performed in Basel. The in-depth analysis on 148 qPCR confirmed cases underlined that BU is a pediatric disease in Africa and that the lesions occur mainly at the limbs with no differences amongst males and females. We obtained information on the exact geographical origin of 136 qPCR positive BU patients through mapping of their houses and farms. Results revealed for the majority of patients residence or agricultural activities close to the Mbam river. Sites of environmental contact of BU patients were screened to search for potential reservoirs of M. ulcerans. At one village water site, DNA of M. ulcerans, was persistently found over more than 2 years, indicating that the pathogen may persist in detritus. Because some of the BU lesions healed very fast, while others showed an impaired healing process, we analyzed tissue samples in detail for the presence of wound healing and scarring biomarkers. Using the histopathological approach, we evaluated the use of markers of cell activation, myofibroblast formation and matrix deposition for the monitoring of the healing of BU lesions. While α-smooth muscle actin-positive myofibroblasts were not found in untreated lesions, they emerged during the healing process. These cells produced abundant extracellular matrix proteins, such as procollagen 1 and tenascin and were found in fibronectin rich areas. After antibiotic treatment many cells, including myofibroblasts, revealed an activated phenotype. Healing wounds showed dermal tissue remodelling by apoptosis, and increased cytokeratin 16 expression in the epidermis. Taken together, the results described in this thesis were obtained by a multidisciplinary approach. They contribute to our understanding of BU epidemiology and transmission, as well as of pathogenesis, wound healing and may eventually help to improve diagnosis, treatment and prevention of BU.

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