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Buruli ulcer is an indolent necrotizing disease of the skin, subcutaneous tissue, and bone that is caused by Mycobacterium ulcerans. Buruli ulcer is presently the third most common mycobacterial disease of humans, after tuberculosis and leprosy, and the least understood of the three. The disease remained largely ignored by many national public health programs, but more recently, it has been recognized as an emerging health problem, primarily due to its frequent disabling and stigmatizing complications. The contribution discusses various aspects of Buruli ulcer, including its geographic distribution, incidence, and prevalence; mode of transmission, pathogenesis, and immunity; clinical manifestations; laboratory diagnosis; differential clinical diagnosis; and treatment.

Buruli ulcer (BU) is a devastating, necrotizing, tropical skin disease caused by infections with Mycobacterium ulcerans. In contrast to other mycobacterioses, BU has been associated with minimal or absent inflammation. However, here we show that in the mouse M. ulcerans induces persistent inflammatory responses with virulence-dependent patterns. Mycolactone-positive, cytotoxic strains are virulent for mice and multiply progressively, inducing both early and persistent acute inflammatory responses. The cytotoxicity of these strains leads to progressive destruction of the inflammatory infiltrates by postapoptotic secondary necrosis, generating necrotic acellular areas with extracellular bacilli released by the lysis of infected phagocytes. The necrotic areas, always surrounded by acute inflammatory infiltrates, expand through the progressive invasion of healthy tissues around the initial necrotic lesions by bacteria and by newly recruited acute inflammatory cells. Our observations show that the lack of inflammatory infiltrates in the extensive areas of necrosis seen in advanced infections results from the destruction of continuously produced inflammatory infiltrates and not from M. ulcerans-induced local or systemic immunosuppression. Whether this is the mechanism behind the predominance of minimal or absent inflammatory responses in BU biopsies remains to be elucidated.Pathogenic mycobacteria are intracellular parasites that are responsible for several clinically important infections in humans and animals. The most frequent mycobacterial infections in humans are caused by Mycobacterium tuberculosis and M. leprae. However, a unique group of mycobacterioses has been emerging and comprises infections caused by M. marinum, M. hemophilum, and M. ulcerans (12). These are slow-growing mycobacteria with some genetic relatedness (71) and common peculiar characteristics. These mycobacteria have optimal growth temperatures of 28 to 33°C and infect primarily the cooler parts of the body, mainly the skin. They have cytotoxic activity (17,56,57) and, as a consequence, produce necrotizing lesions (3,7,12,72).Buruli ulcer (BU), caused by M. ulcerans, has become the third most prevalent mycobacteriosis throughout the world, after tuberculosis and leprosy, with higher incidence in the tropical regions of western and central Africa (11,74). BU is a devastating skin disease characterized by different clinical forms, including nonulcerative subcutaneous nodules, papules, edema, and plaques, that can eventually progress to ulcerative forms and often to extensive necrotic lesions (11, 74). Osteomyelitis has been described as a complication of M. ulcerans infection, particularly in some African regions (11,39).Genetic analyses showed that M. marinum and M. ulcerans are very closely related to M. tuberculosis (71), a mycobacterium that also exhibits some cytotoxicity (14,19,37,43), which contributes to the necrotic lesions seen in tuberculosis (43). Recently, genes in the extRD1 region have been implicated in the cytotoxic activity of M...

Hospital data show that Buruli ulcer is highly endemic in southern Benin.

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 FindingsOne 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.ConclusionStrain 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.

Mycobacterium ulcerans infection, or Buruli ulcer, is the third most frequent mycobacterial disease in humans, often causing serious deformities and disability. The disease is most closely associated with tropical wetlands, especially in west and central Africa. Most investigators believe that the aetiological agent proliferates in mud beneath stagnant waters. Modes of transmission may involve direct contact with the contaminated environment, aerosols from water surfaces, and water-dwelling fauna (e.g. insects). Person-to-person transmission is rare. Trauma at the site of skin contamination by M. ulcerans appears to play an important role in initiating disease. Once introduced into the skin or subcutaneous tissue, M. ulcerans multiplies and produces a toxin that causes necrosis. However, the type of disease induced varies from a localised nodule or ulcer, to widespread ulcerative or non-ulcerative disease and osteomyelitis.Although culture of M. ulceransfrom a patient was first reported in 1948, attempts to culture the mycobacterium from many specimens of flora and fauna have been unsuccessful. Failure to cultivate this organism from nature may be attributable to inadequate sampling, conditions of transport, decontamination and culture of this fastidious heat-sensitive organism, and to along generation time relative to that of other environmental mycobacteria. Nevertheless, recent molecular studies using specific primers have revealed M. ulcerans in water, mud, fish and insects. Although no natural reservoir has been found, the possibility that M. ulcerans may colonise microfauna such as free-living amoebae has not been investigated. The host range of experimental infection by M. ulcerans includes lizards, amphibians, chick embryos, possums, armadillos, rats, mice and cattle. Natural infections have been observed only in Australia, in koalas, ringtail possums and a captive alpaca. The lesions were clinically identical to those observed in humans. Mycobacterium ulcerans infection is a rapidly re-emerging disease in some developing tropical countries. The re-emergence may be related to environmental and socioeconomic factors, for example, deforestation leading to increased flooding, and population expansion without improved agricultural techniques, thus putting more people at risk. Eradication of diseases related to these factors is difficult. Whether wild animals have a role in transmission is an important question that, to date, has been virtually unexplored. To address this question, surveys of wild animals are urgently required in those areas in which Buruli ulcer is endemic. KeywordsAlpacas -Aquatic insects -Buruli ulcer -Environment -Fish -Koalas -Mycobacteria -Mycobacterium ulcerans -Possums-Water. Bev. sci. teck Off.int.Epa.. 20 (1)

SummaryMycobacterium ulcerans produces an extracellular cutaneous infection (Buruli ulcer) characterized by immunosuppression. This is in stark contrast to all other pathogenic Mycobacteria species that cause intracellular, granulomatous infections. The unique mycobacterial pathology of M. ulcerans infection is attributed to a plasmid-encoded immunomodulatory macrolide toxin, mycolactone. In this article we explore the role of mycolactone in the virulence of M. ulcerans using mycolactone and genetically defined mycolactone negative mutants. In a guinea pig infection model wild-type (WT) M. ulcerans produces an extracellular infection whereas mycolactone negative mutants produce an intracellular inflammatory infection similar to that of Mycobacterium marinum . Although mycolactone negative mutants are avirulent, they persist for at least 6 weeks. Chemical complementation of M. ulcerans mutants with mycolactone restores WT M. ulcerans pathology. Mycolactone negative mutants are capable of growth within macrophages in vitro whereas macrophages are killed by WT M. ulcerans . The ability of mycolactone to caused delayed cell death via apoptosis has been reported. However, mycolactone also causes cell death via necrosis. In vitro mycolactone has antiphagocytic properties. Neither WT M. ulcerans nor mycolactone negative strains are strong neutrophil attractants. These results suggest that mycolactone is largely responsible for the unique pathology produced by M. ulcerans .

Mycobacterium ulcerans is the etiologic agent of Buruli ulcer (BU), an emerging tropical skin disease. Virulent M. ulcerans secretes mycolactone, a cytotoxic exotoxin with a key pathogenic role. M. ulcerans in biopsy specimens has been described as an extracellular bacillus. In vitro assays have suggested a mycolactoneinduced inhibition of M. ulcerans uptake by macrophages in which its proliferation has not been demonstrated. Therefore, and uniquely for a mycobacterium, M. ulcerans has been classified as an extracellular pathogen. In specimens from patients and in mouse footpad lesions, extracellular bacilli were concentrated in central necrotic acellular areas; however, we found bacilli within macrophages in surrounding inflammatory infiltrates. We demonstrated that mycolactone-producing M. ulcerans isolates are efficiently phagocytosed by murine macrophages, indicating that the extracellular location of M. ulcerans is not a result of inhibition of phagocytosis. Additionally, we found that M. ulcerans multiplies inside cultured mouse macrophages when low multiplicities of infection are used to prevent early mycolactone-associated cytotoxicity. Following the proliferation phase within macrophages, M. ulcerans induces the lysis of the infected host cells, becoming extracellular. Our data show that M. ulcerans, like M. tuberculosis, is an intracellular parasite with phases of intramacrophage and extracellular multiplication. The occurrence of an intramacrophage phase is in accordance with the development of cell-mediated and delayed-type hypersensitivity responses in BU patients.Mycobacterium ulcerans is the etiologic agent of Buruli ulcer (BU), an emerging, devastating, difficult-to-treat skin disease reported in many countries, mostly in tropical areas (16), and BU has become the third most common mycobacterial infection in humans after tuberculosis and leprosy. BU assumes various nonulcerative clinical forms that can progress to ulcers.M. ulcerans (26, 41, 47, 59), M. tuberculosis (24, 38, 42), M. marinum (25,57), and M. haemophilum (23) are known to have cytotoxic activity, M. ulcerans being the most cytotoxic of all known mycobacteria. The M. ulcerans toxin is a mycolactone, a unique polyketide lipid exotoxin that has a potent destructive activity for cells that provokes the extensive necrotic lesions characteristic of BU (26). Mycolactone is considered to be the major virulence factor of this pathogen (1, 26, 41).Intracellular parasites are defined on the basis of their lifestyles in the infected hosts and of the types of immune responses elicited (7, 37): they live and multiply predominantly within host cells, typically macrophages, and therefore are able to survive and grow within cultured macrophages. The host immune response against intramacrophage parasites involves mechanisms of cell-mediated immunity (CMI) accompanied by delayed-type hypersensitivity (DTH).Genetic analysis places M. ulcerans very close to M. marinum and M. tuberculosis (71), two species of mycobacteria that are typical intracellular p...