Abstract
Background Mycobacterium ulcerans, a slow-growing environmental bacterium, is the etiologic agent of Buruli ulcer, a necrotic skin disease. Skin lesions are caused by mycolactone, the main virulence factor of M. ulcerans, with dermonecrotic (destruction of the skin and soft tissues) and immunosuppressive activities. This toxin is secreted in vesicles that enhance its biological activities. Nowadays, it is well established that the main reservoir of the bacilli is localized in the aquatic environment where the bacillus may be able to colonize different niches. Here we report that plant polysaccharides stimulate M. ulcerans growth and are implicated in toxin synthesis regulation.Methodology/Principal FindingsIn this study, by selecting various algal components, we have identified plant-specific carbohydrates, particularly glucose polymers, capable of stimulating M. ulcerans growth in vitro. Furthermore, we underscored for the first time culture conditions under which the polyketide toxin mycolactone, the sole virulence factor of M. ulcerans identified to date, is down-regulated. Using a quantitative proteomic approach and analyzing transcript levels by RT-qPCR, we demonstrated that its regulation is not at the transcriptional or translational levels but must involve another type of regulation. M. ulcerans produces membrane vesicles, as other mycobacterial species, in which are the mycolactone is concentrated. By transmission electron microscopy, we observed that the production of vesicles is independent from the toxin production. Concomitant with this observed decrease in mycolactone production, the production of mycobacterial siderophores known as mycobactins was enhanced.Conclusions/SignificanceThis work is the first step in the identification of the mechanisms involved in mycolactone regulation and paves the way for the discovery of putative new drug targets in the future.
Highlights
Mycobacterium ulcerans, a slow-growing environmental bacterium, is the causative agent of Buruli ulcer, a severe infectious skin disease
This polyketide toxin has intense cytotoxic activity in vitro, affecting numerous cell types [5], is thought to have immune-modulatory activities decreasing the efficiency of the immune system [6] and inhibits M. ulcerans uptake by phagocytes, which led to the interpretation that M. ulcerans was an extracellular pathogen
We brought out for the first time that addition of specific carbohydrate to culture medium induces the downregulation of the toxin. This decrease in toxin production is correlated with the activation of the iron acquisition pathway, especially by siderophore production. These results show that M. ulcerans adapts its metabolism to culture conditions, which probably reflect its adaptation in its natural habitats
Summary
Mycobacterium ulcerans, a slow-growing environmental bacterium, is the causative agent of Buruli ulcer, a severe infectious skin disease. This disease mainly occurs in humid tropical zones, especially in West African countries. The massive tissue destructions forming large painless ulcers with undermined edges that could touch the bone tissue are induced by a bacterial toxin, the mycolactone, which remains, the main virulence factor [3,4]. Skin lesions are caused by mycolactone, the main virulence factor of M. ulcerans, with dermonecrotic (destruction of the skin and soft tissues) and immunosuppressive activities This toxin is secreted in vesicles that enhance its biological activities. We report that plant polysaccharides stimulate M. ulcerans growth and are implicated in toxin synthesis regulation
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