Mycolactone has been shown to inhibit the responses of macrophages and activated T-cells in-vitro, to inhibit phagocytosis by murine macrophages, to induce lysis of cultured macrophages after a transient intracellular growth as well as to impair the production of TNF-alpha by these cells and to inhibit induction of chemokine secretion by dendritic cells. The necrosis is explained by cytotoxic properties of mycolactone but the paucity of inflammatory cells despite extensive skin damage may be due to its immunosuppressive properties. The classic histological feature of human Buruli ulcer lesions is subcutaneous fatty necrosis with clumps of AFB in the absence of inflammatory cells. Mycolactone has also been associated with vacuolar nerve tissue damage in mice and this observation may account for the painlessness of Buruli ulcer lesions. Histologically these lesions showed significant apoptotic cell death, a feature which has been observed in human lesions. Chemical complementation of this mutant with mycolactone restored virulence. ulcerans was phagocytosed by macrophages and stimulated a typical mycobacterial inflammatory response, including granuloma formation. Although direct inoculation of mycolactone intradermally into guinea pigs caused necrotic lesions similar to those produced by the injection of live organisms, an isogenic toxin-negative mutant M. George et al demonstrated that injection of 100 µg of mycolactone was sufficient to cause characteristic ulcers in guinea pig skin and that histopathological changes could be detected with 10 µg. Various elegant in-vitro and in-vivo studies in mice and guinea pigs have demonstrated that this polyketide toxin is central to the pathogenesis of M. 10.1371/001 Figure 1 Chemical structure of mycolactone A/B showing the lactone core ring and polyketide side chains. The toxin causes cell cycle arrest in the G0/G1 phase within 48 hours, proceeding to cell death by apoptosis after 72 hours. Mycolactone causes a cytopathic effect on mouse fibroblast L929 cells characterised by cytoskeletal rearrangement with rounding up and subsequent detachment from tissue culture plates within 48 hours. Subsequently mycolactone has been characterised as a 743 Da molecule consisting of a 12-membered ring macrolide with two polyketide derived side chains ( figure 1) synthesised by giant polyketide synthases and polyketide modifying enzymes whose genes are carried on two identical copies of a 174 kb plasmid known as pMUM001. Initial attempts to isolate this substance were frustrated by low yields from cultures until the late 1990s when a toxin called mycolactone was partly purified and its chemical structure defined. ulcerans culture filtrate could produce similar lesions after injection into guinea pig skin. This histopathology led to the suggestion that Mu causes disease by secretion of a toxin which can destroy human tissue and inhibit the development of local inflammation. Histology shows clumps of acid fast bacilli in areas of subcutaneous fatty necrosis with acute and chronic inflammation remote from the necrotic areas. The classic lesion is a painless nodule which breaks down centrally to form an ulcer with undermined edges. Mycobacterium ulcerans (Mu) disease (Buruli ulcer) is common in humid rural tropical areas mainly in West Africa and predominantly affects children between 5 and 15 years of age.
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