Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Hospital Provincial del Centenario, Universidad Nacional de Rosario, CONICET, Rosario, Argentina.
Microb Pathog. 2012 Jan;52(1):85-91. doi: 10.1016/j.micpath.2011.10.008. Epub 2011 Nov 4.
Histotoxic strains of Clostridium perfringens cause human gas gangrene, a devastating infection during which potent tissue-degrading toxins are produced and secreted. Although this pathogen only grows in anaerobic-nutrient-rich habitats such as deep wounds, very little is known regarding how nutritional signals influence gas gangrene-related toxin production. We hypothesize that sugars, which have been used throughout history to prevent wound infection, may represent a nutritional signal against gas gangrene development. Here we demonstrate, for the first time, that sugars (sucrose, glucose) inhibited the production of the main protein toxins, PLC (alpha-toxin) and PFO (theta-toxin), responsible for the onset and progression of gas gangrene. Transcription analysis experiments using plc-gusA and pfoA-gusA reporter fusions as well as RT-PCR analysis of mRNA transcripts confirmed that sugar represses plc and pfoA expression. In contrast an isogenic C. perfringens strain that is defective in CcpA, the master transcription factor involved in carbon catabolite response, was completely resistant to the sugar-mediated inhibition of PLC and PFO toxin production. Furthermore, the production of PLC and PFO toxins in the ccpA mutant strain was several-fold higher than the toxin production found in the wild type strain. Therefore, CcpA is the primary or unique regulatory protein responsible for the carbon catabolite (sugar) repression of toxin production of this pathogen. The present results are analyzed in the context of the role of CcpA for the development and aggressiveness of clostridial gas gangrene and the well-known, although poorly understood, anti-infective and wound healing effects of sugars and related substances.
组织坏死性梭菌的组织毒性株可引起人类气性坏疽，这是一种破坏性的感染，在此过程中会产生并分泌强效的组织降解毒素。尽管该病原体仅在厌氧营养丰富的环境中生长，例如深部伤口，但对于营养信号如何影响气性坏疽相关毒素产生的机制却知之甚少。我们假设，糖在历史上一直被用于预防伤口感染，可能代表了一种预防气性坏疽发展的营养信号。在这里，我们首次证明，糖（蔗糖、葡萄糖）可抑制主要蛋白毒素 PLC（α-毒素）和 PFO（θ-毒素）的产生，这些毒素负责气性坏疽的发作和进展。使用 plc-gusA 和 pfoA-gusA 报告基因融合的转录分析实验以及 mRNA 转录本的 RT-PCR 分析证实，糖可抑制 plc 和 pfoA 的表达。相比之下，一个在 CcpA 中缺失的同源产气荚膜梭菌菌株，CcpA 是参与碳分解代谢物反应的主要转录因子，对糖介导的 PLC 和 PFO 毒素产生抑制完全具有抗性。此外，ccpA 突变株中 PLC 和 PFO 毒素的产生比野生型菌株中的毒素产生高几倍。因此，CcpA 是主要或唯一的调节蛋白，负责该病原体的碳分解代谢物（糖）对毒素产生的抑制。目前的结果是在 CcpA 对梭状芽胞杆菌气性坏疽的发展和侵袭性的作用以及糖和相关物质的众所周知但知之甚少的抗感染和伤口愈合作用的背景下进行分析的。
