Mycobacterium ulcerans (Buruli ulcer)
Buruli ulcer (BU), also known as tropical ulcer, is an emerging necrotic skin disease caused by Mycobacterium ulcerans. M. ulcerans is the third most important mycobacterial pathogen of man after M. tuberculosis and M. leprae. It is found in water-dwelling insects, snails and fish. M. ulcerans also has been described in native Australian animals including the koala, possums and the long-footed potoroo. Transmission to humans is by an unknown mechanism, presumably as a consequence of local trauma, although recent evidence suggests that aquatic insects may be the natural reservoir and their bite may transmit the disease to humans. BU presents as a chronic, essentially painless skin ulcer with whitish or yellowish base that usually starts as small nodules which subsequently ulcerate. Most lesions are located on the extremities and occur among children living near wetlands and rain forests in rural tropical environments. Bones and joints may be affected and cases of osteomyelitis have been reported with increasing frequency. Although most ulcers eventually heal, poorly managed patients eventually present with scars, oedema, and local deformities including disabling contractures. M. ulcerans secretes a polyketide macrolide toxin, mycolactone, a virulence factor which has both necrotising and immunosuppressive properties. Other toxins and virulence determinants such as phospholipase C may also play a role. BU is associated with severe illness and permanent disabilities in >25% of patients. Currently, the only treatment for lesion of M. ulcerans infection is wide surgical resection. Unfortunately, many patients do not present until there is extensive and disfiguring ulceration.
BU is currently endemic in West Africa. It is also reported from the Americas, Asia, Australia and Papua New Guinea. Environmental changes that promote flooding, such as deforestation, dam construction and irrigation systems, often are associated with outbreaks of BU. The global burden of BU is, however, unknown. A report from Ghana estimated a national prevalence of 20.7/100 000 in 1999. In some West African communities, BU was reported to have replaced TB and leprosy as the most prevalent mycobacterial disease, affecting up to 22% of the population. The rising incidence of the disease, its predilection for poor rural communities, the cost of complex surgical treatment, the lost productivity during illness, and the reduced fitness after recovery combine to make BU a major economic burden in West Africa. Vaccines
Two large randomized controlled trials of BCG vaccination for the prevention of BU were conducted in Uganda during the late 1960s. The overall protective efficacy of BCG against M. ulcerans infection was 47%, but the effect was short lived, ranging from six months in one study to one year in the other. BCG was shown to be protective in a mouse model of M. ulcerans using a small challenge inoculum, but protection was overcome when using larger challenge doses. Taken together, these results strongly suggest that a new vaccine is needed for the prevention of BU. To our knowledge, no private investment is devoted to the research on BU vaccines at present, and most BU research activities are coordinated by the Global Buruli Ulcer Initiative.