Regulation of mycolactone, the Mycobacterium ulcerans toxin, depends on nutrient source.
Regulation of mycolactone, the Mycobacterium ulcerans toxin, depends on nutrient source.
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DOI：
10.1371/journal.pntd.0002502
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发表时间：
2013-11
影响因子：
3.8
通讯作者：
Marsollier L
中科院分区：
文献类型：
--
作者：
Deshayes C;Angala SK;Marion E;Brandli I;Babonneau J;Preisser L;Eyangoh S;Delneste Y;Legras P;De Chastellier C;Stinear TP;Jackson M;Marsollier L
溃疡分枝杆菌是一种生长缓慢的环境细菌，是一种坏死性皮肤病布鲁里溃疡的病因。皮肤病变是由溃疡分枝杆菌的主要毒力因子霉菌内酯引起的，具有皮肤坏死（破坏皮肤和软组织）和免疫抑制活性。这种毒素在囊泡中分泌，增强其生物活性。目前，已经确定的是，芽孢杆菌的主要储存库是在水生环境中，在那里芽孢杆菌可能能够定植不同的生态位。在这里，我们报道植物多糖刺激溃疡分枝杆菌生长，并参与毒素合成调节。在这项研究中，通过选择各种藻类成分，我们已经确定了植物特异性碳水化合物，特别是葡萄糖聚合物，能够刺激溃疡分枝杆菌的体外生长。此外，我们首次强调了迄今为止确定的溃疡分枝杆菌唯一毒力因子聚酮毒素霉菌内酯下调的培养条件。使用定量蛋白质组学方法并通过RT-qPCR分析转录水平，我们证明其调控不在转录或翻译水平，而必须涉及另一种类型的调控。溃疡分枝杆菌像其他分枝杆菌一样产生膜囊泡，其中集中了菌内酯。通过透射电镜，我们观察到囊泡的产生与毒素的产生是独立的。伴随这种观察到的菌内酯生产减少，分枝杆菌铁载体的生产被称为分枝杆菌素被增强。这项工作是鉴定霉菌内酯调节机制的第一步，并为未来发现假定的新药物靶点铺平了道路。菌内酯是一种聚酮类细胞毒素，是造成布鲁里溃疡大面积皮肤溃疡的主要毒力因子。这种疾病主要发生在潮湿的热带地区，特别是在西非国家，是由溃疡分枝杆菌感染引起的，这是一种生长缓慢的环境分枝杆菌。这种毒素对皮肤、软组织和骨骼有破坏性影响。在本研究中，我们首次发现在培养基中添加特定的碳水化合物可以诱导毒素的下调。此外，毒素产生的减少与铁获取途径的激活有关，特别是通过铁载体的产生。这些结果表明，溃疡分枝杆菌使其代谢适应培养条件，这可能反映了其对自然栖息地的适应。这项工作是了解毒素调节的第一步，这是更好地理解布鲁里溃疡生理病理和确定推定治疗靶点的关键问题。
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. In 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. This 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. Mycolactone, a polyketide cytotoxic toxin, is the key virulence factor responsible for large skin ulcers in Buruli ulcer. This disease, mainly occurring in humid tropical zones, especially in West African countries, is due to infection by Mycobacterium ulcerans, a slow-growing environmental mycobacterium. The toxin has destructive effects on the skin, soft tissues and bones. In this study, we brought out for the first time that addition of specific carbohydrate to culture medium induces the down-regulation of the toxin. Furthermore, 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. This work is the first step in toxin regulation understanding which is a key issue for a better comprehension of Buruli ulcer physiopathology and the identification of putative therapeutic targets.
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DOI：
10.1016/0035-9203(71)90090-3
发表时间：
1971-01-01
影响因子：
2.2
作者：
通讯作者：
--
影响因子：
3.6
作者：
Hélaine, S;Carbonnelle, E;Pelicic, V
通讯作者：
Pelicic, V
影响因子：
4.4
作者：
Eddyani, M;Ofori-Adjei, D;Portaels, F
通讯作者：
Portaels, F
影响因子：
3.2
作者：
Chavadi, Sivagami Sundaram;Stirrett, Karen L.;Quadri, Luis E. N.
通讯作者：
Quadri, Luis E. N.
影响因子：
6.1
作者：
Hsu, Hsien-Yeh;Hua, Kuo-Feng;Chao, Louis Kuoping
通讯作者：
Chao, Louis Kuoping