Phagocytosis of Mycobacterium ulcerans in the course of rifampicin and streptomycin chemotherapy in Buruli ulcer lesions

BACKGROUND: Infection with Mycobacterium ulcerans involves a devastating skin disease called Buruli ulcer (BU). Currently, dual therapy with rifampicin and streptomycin (R/S) for 8 weeks as well as surgery are the standard treatments. OBJECTIVES: To elucidate the processes taking place in BU lesions in the course of chemotherapy we performed an in-depth histological analysis of lesions after 4 weeks of R/S treatment and compared results with findings in untreated lesions and lesions treated for 8 weeks. METHODS: Tissue specimens were collected from patients who had no treatment and from patients after 4 and 8 weeks of R/S treatment. The main features evaluated were local immune responses, histopathological alterations and bacterial distribution. RESULTS: After 4 weeks of R/S treatment we observed a large proportion of mycobacteria inside macrophages, occasionally forming globus-like aggregations. While distinct bands of inflammatory leucocytes surrounded the necrotic core in an ulcer and early granuloma formation was apparent in the healthy-appearing margins, acute cellular infiltration covering the whole lesion had developed in a nodular lesion. In contrast, ulcerative lesions after 8 weeks of chemotherapy showed intra- and extracellular bacterial debris as well as the presence of extensive chronic infiltrates forming huge granulomas. CONCLUSIONS: R/S treatment of BU results in a rapid onset of local cellular immune responses associated with phagocytosis of the extracellular M. ulcerans. This may be related to declining levels of the macrolide toxin mycolactone in the tissue, thus leading to an enhanced chemotherapy-induced clearance of the infection