title: Cellular immunity confers transient protection in experimental Buruli ulcer following BCG or mycolactone-negative Mycobacterium ulcerans vaccination.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  In 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
  The 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.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Fraga
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Martins
authors.forename: Egídio
authors.initials: E
authors.lastname: Torrado
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Françoise
authors.initials: F
authors.lastname: Portaels
authors.forename: Manuel T
authors.initials: MT
authors.lastname: Silva
authors.forename: António G
authors.initials: AG
authors.lastname: Castro
authors.forename: Jorge
authors.initials: J
authors.lastname: Pedrosa
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage*; D054312:Buruli Ulcer / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular; D018942:Macrolides; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019911:Mycobacterium ulcerans / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D016207:Cytokines; D018942:Macrolides; C117218:mycolactone; D052247:Nitric Oxide Synthase Type II