Background: Buruli ulcer (BU) is a debilitating skin disease characterised by necrosis of subcutaneous tissue. The causative agent, Mycobacterium ulcerans, produces the immunosuppressive toxin mycolactone as its major virulence factor. The mode of transmission is not well understood and there is currently no vaccine. This study utilised a low-dose, bioluminescent murine BU infection model to examine a protein-based vaccine targeting the mycolactone production pathway.
Methods and Results: Previous studies by Roupie et al (2014) and Pidot et al (2010) identified an immunogenic enoyl reductase (ER) domain within the type I polyketide synthases responsible for producing mycolactone. In this study, BALB/c mice were vaccinated with recombinant ER coupled to a lipopeptide TLR-2 agonist (R4Pam2Cys). Prior to BU-challenge, mice vaccinated with ER+R4Pam2Cys had significantly higher ER-specific antibody responses than mice vaccinated with ER alone. The mice were challenged using a recently developed low-dose BU infection method. Mouse-tails were coated in a bioluminescent strain of M. ulcerans and the contaminated skin was subcutaneously punctured with a sterile needle. In this model, mice have an infectious dose-50 of 3-colony forming units (CFU). In vivo imaging is used to monitor disease progression by detecting light emitted by the bacteria. This study is ongoing. To date, less ER+R4Pam2Cys vaccinated mice have succumbed to infection compared to unvaccinated mice.
Conclusions: This infection model is the first to highlight the low infectious dose required for M. ulcerans infection and utilises a novel quantitative method to monitor Buruli ulcer progression. This vaccine induces high pathogen-specific antibody titres. Outcomes of this study will include a better understanding of the immune correlates for a protective BU-vaccine.