Cellular Immunity Confers Transient Protection in Experimental Buruli Ulcer following BCG or Mycolactone-Negative Mycobacterium ulcerans Vaccination

Alexandra G Fraga,Teresa G Martins,Françoise Portaels,António G Castro,Manuel T Silva,Egídio Torrado,Kris Huygen,Jorge Pedrosa

doi:10.1371/journal.pone.0033406

Alexandra G Fraga, Teresa G Martins + Show 6 more

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https://doi.org/10.1371/journal.pone.0033406

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Abstract

BackgroundBuruli ulcer (BU) is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. There is no specific vaccine against BU but reports show some degree of cross-reactive protection conferred by M. bovis BCG immunization. Alternatively, an M. ulcerans-specific immunization could be a better preventive strategy.Methodology/Principal FindingsIn this study, we used the mouse model to characterize the histological and cytokine profiles triggered by vaccination with either BCG or mycolactone-negative M. ulcerans, followed by footpad infection with virulent M. ulcerans. We observed that BCG vaccination significantly delayed the onset of M. ulcerans growth and footpad swelling through the induction of an earlier and sustained IFN-γ T cell response in the draining lymph node (DLN). BCG vaccination also resulted in cell-mediated immunity (CMI) in M. ulcerans-infected footpads, given the predominance of a chronic mononuclear infiltrate positive for iNOS, as well as increased and sustained levels of IFN-γ and TNF. No significant IL-4, IL-17 or IL-10 responses were detected in the footpad or the DLN, in either infected or vaccinated mice. Despite this protective Th1 response, BCG vaccination did not avoid the later progression of M. ulcerans infection, regardless of challenge dose. Immunization with mycolactone-deficient M. ulcerans also significantly delayed the progression of footpad infection, swelling and ulceration, but ultimately M. ulcerans pathogenic mechanisms prevailed.Conclusions/SignificanceThe delay in the emergence of pathology observed in vaccinated mice emphasizes the relevance of protective Th1 recall responses against M. ulcerans. In future studies it will be important to determine how the transient CMI induced by vaccination is compromised.

Highlights

Buruli ulcer (BU), a neglected tropical disease caused by infection with Mycobacterium ulcerans, initially starts off as a nonulcerative cutaneous lesion that can eventually progress into an ulcer if left untreated
Confirming previous findings by Tanghe et al [27], prior BCG immunization was responsible for a reduction in the number of viable bacilli in the infected tissue, during which macroscopic lesions were absent in the footpads of BCG-vaccinated mice [18,21,22], with a 4 log10 reduction observed at day 52 post-infection (Figure 1B)
To characterize the type of immune response associated with the BCG-induced delay of M. ulcerans disease, we carried out a comparative analysis of cytokine kinetics in footpads

Summary

Introduction

Buruli ulcer (BU), a neglected tropical disease caused by infection with Mycobacterium ulcerans, initially starts off as a nonulcerative cutaneous lesion that can eventually progress into an ulcer if left untreated. BU has become an emerging health problem in many endemic countries and the escalating morbidity rate has an overwhelming socioeconomic burden on the affected populations [2]. There is no vaccine against M. ulcerans infection and the classical approach for BU treatment has been surgical, involving wide excision of necrotic areas and surrounding healthy tissues [7,8,9]. Buruli ulcer (BU) is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. An M. ulcerans-specific immunization could be a better preventive strategy

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