mycolactone and Skin-Diseases--Bacterial

Buruli ulcer is caused by

Topics: Africa, Western; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Humans; Macrolides; Mycobacterium Infections; Mycobacterium ulcerans; Neglected Diseases; Polymerase Chain Reaction; Rifampin; Skin Diseases, Bacterial; Streptomycin

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 mycolactone-induced 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.

Topics: Animals; Bacterial Toxins; Cells, Cultured; Disease Models, Animal; Female; Foot; Histocytochemistry; Humans; Macrolides; Macrophages; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Phagocytosis; Skin Diseases, Bacterial; Skin Ulcer

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe human skin disease that occurs primarily in Africa and Australia. Infection with M. ulcerans results in persistent severe necrosis without an acute inflammatory response. The presence of histopathological changes distant from the site of infection suggested that pathogenesis might be toxin mediated. A polyketide-derived macrolide designated mycolactone was isolated that causes cytopathicity and cell cycle arrest in cultured L929 murine fibroblasts. Intradermal inoculation of purified toxin into guinea pigs produced a lesion similar to that of Buruli ulcer in humans. This toxin may represent one of a family of virulence factors associated with pathology in mycobacterial diseases such as leprosy and tuberculosis.

Topics: Animals; Bacterial Toxins; Cell Cycle; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Female; Guinea Pigs; L Cells; Macrolides; Mass Spectrometry; Mice; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Necrosis; Skin; Skin Diseases, Bacterial; Virulence