Local Cellular Immune Responses and Pathogenesis of Buruli Ulcer Lesions in the Experimental Mycobacterium Ulcerans Pig Infection Model

BACKGROUND: Buruli ulcer is a neglected tropical disease of the skin that is caused by infection with Mycobacterium ulcerans. We recently established an experimental pig (Sus scrofa) infection model for Buruli ulcer to investigate host-pathogen interactions, the efficacy of candidate vaccines and of new treatment options. METHODOLOGY/PRINCIPAL FINDINGS: Here we have used the model to study pathogenesis and early host-pathogen interactions in the affected porcine skin upon infection with mycolactone-producing and non-producing M. ulcerans strains. Histopathological analyses of nodular lesions in the porcine skin revealed that six weeks after infection with wild-type M. ulcerans bacteria extracellular acid fast bacilli were surrounded by distinct layers of neutrophils, macrophages and lymphocytes. Upon ulceration, the necrotic tissue containing the major bacterial burden was sloughing off, leading to the loss of most of the mycobacteria. Compared to wild-type M. ulcerans bacteria, toxin-deficient mutants caused an increased granulomatous cellular infiltration without massive tissue necrosis, and only smaller clusters of acid fast bacilli. CONCLUSIONS/SIGNIFICANCE: In summary, the present study shows that the pathogenesis and early immune response to M. ulcerans infection in the pig is very well reflecting BU disease in humans, making the pig infection model an excellent tool for the profiling of new therapeutic and prophylactic interventions.