Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer.

The necrotising skin infection Buruli ulcer is at present the third most common human mycobacteriosis worldwide, after tuberculosis and leprosy. Buruli ulcer is an emergent disease that is predominantly found in humid tropical regions. There is no vaccine against Buruli ulcer and its treatment is difficult. In addition to the huge social effect, Buruli ulcer is of great scientific interest because of the unique characteristics of its causative organism, Mycobacterium ulcerans. This pathogen is genetically very close to the typical intracellular parasites Mycobacterium marinum and Mycobacterium tuberculosis. We review data supporting the interpretation that M ulcerans has the essential hallmarks of an intracellular parasite, producing infections associated with immunologically relevant inflammatory responses, cell-mediated immunity, and delayed-type hypersensitivity. This interpretation judges that whereas M ulcerans behaves like the other pathogenic mycobacteria, it represents an extreme in the biodiversity of this family of pathogens because of its higher cytotoxicity due to the secretion of the exotoxin mycolactone. The acceptance of the interpretation that Buruli ulcer is caused by an intracellular parasite has relevant prophylactic and therapeutic implications, rather than representing the mere attribution of a label with academic interest, because it prompts the development of vaccines that boost cell-mediated immunity and the use of chemotherapeutic protocols that include intracellularly active antibiotics.

Buruli ulcer disease: prospects for a vaccine.

Buruli ulcer disease (BUD), caused by Mycobacterium ulcerans, is a neglected bacterial infection of the poor in remote rural areas, mostly affecting children. BUD is a mutilating disease leading to severe disability; it is the third most common mycobacterial infection in immunocompetent people after tuberculosis and leprosy. It is most endemic in West Africa, but cases have been reported from more than 30 countries. Treatment with antibiotics is possible, long-lasting and requires injections; there are cases of treatment failures, and the disease is prone to resistance. A vaccine against M. ulcerans would protect persons at risk in highly endemic areas, and could be used as a therapeutic vaccine to shorten the duration of treatment and prevent relapses. There is considerable evidence supporting the notion that generation of a vaccine is feasible. This article reviews the present state of the art with special emphasis on the immunology of the infection and the prospects for development of a vaccine.

First cultivation and characterization of Mycobacterium ulcerans from the environment.

BACKGROUND: Mycobacterium ulcerans disease, or Buruli ulcer (BU), is an indolent, necrotizing infection of skin, subcutaneous tissue and, occasionally, bones. It is the third most common human mycobacteriosis worldwide, after tuberculosis and leprosy. There is evidence that M. ulcerans is an environmental pathogen transmitted to humans from aquatic niches; however, well-characterized pure cultures of M. ulcerans from the environment have never been reported. Here we present details of the isolation and characterization of an M. ulcerans strain (00-1441) obtained from an aquatic Hemiptera (common name Water Strider, Gerris sp.) from Benin. METHODOLOGY/PRINCIPAL FINDINGS: One culture from a homogenate of a Gerris sp. in BACTEC became positive for IS2404, an insertion sequence with more than 200 copies in M. ulcerans. A pure culture of M. ulcerans 00-1441 was obtained on Löwenstein-Jensen medium after inoculation of BACTEC culture in mouse footpads followed by two other mouse footpad passages. The phenotypic characteristics of 00-1441 were identical to those of African M. ulcerans, including production of mycolactone A/B. The nucleotide sequence of the 5' end of 16S rRNA gene of 00-1441 was 100% identical to M. ulcerans and M. marinum, and the sequence of the 3' end was identical to that of the African type except for a single nucleotide substitution at position 1317. This mutation in M. ulcerans was recently discovered in BU patients living in the same geographic area. Various genotyping methods confirmed that strain 00-1441 has a profile identical to that of the predominant African type. Strain 00-1441 produced severe progressive infection and disease in mouse footpads with involvement of bone. CONCLUSION: Strain 00-1441 represents the first genetically and phenotypically identified strain of M. ulcerans isolated in pure culture from the environment. This isolation supports the concept that the agent of BU is a human pathogen with an environmental niche.