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

Miriam Bolz,Marie-Thérèse Ruf,Gerd Pluschke,Nicolas Ruggli,Nicole Borel,Christian Johnson

doi:10.1371/journal.pntd.0004678

Miriam Bolz, Marie-Thérèse Ruf + Show 4 more

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https://doi.org/10.1371/journal.pntd.0004678

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Abstract

BackgroundBuruli 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 FindingsHere 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/SignificanceIn 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.

Highlights

Buruli ulcer (BU) is a slow progressing, necrotising disease of the skin that mainly affects rural African communities [1,2] and is caused by Mycobacterium ulcerans
Buruli ulcer is a necrotizing ulcerative disease of the skin and underlying tissue caused by infection with Mycobacterium ulcerans
Because patients often present late to health facilities, early stages of Buruli ulcer are only insufficiently described by histopathology

Summary

Introduction

Buruli ulcer (BU) is a slow progressing, necrotising disease of the skin that mainly affects rural African communities [1,2] and is caused by Mycobacterium ulcerans. The major hallmarks of M. ulcerans infection, which are used for histopathological confirmation of clinical diagnosis, are the presence of coagulative necrosis, fat cell ghosts, epidermal hyperplasia and extracellular clusters of acid fast bacilli (AFB) in the absence of major inflammatory infiltrates in central parts of the lesions [5,6]. 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

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