Identification of host-adapted metabolic functions important for Yersinia pseudotuberculosis virulence

鉴定对假结核耶尔森菌毒力重要的宿主适应代谢功能

• 批准号: 71739215
• 负责人: Professorin Dr. Petra Dersch
• 金额: --
• 依托单位: Institut für Systembiotechnologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/71739215?language=en
• 关键词: Identification; host; adapted; metabolic; functions

Initial colonization of the gut and subsequent penetration of the intestinal epithelial layer by the enteric pathogen Yersinia pseudotuberculosis demands expression of a special set of early-stage virulence genes, whereas persistence and multiplication in subepithelial tissues and organs requires synthesis of other pathogenicity factors, e.g. the antiphagocytic Yop proteins. A complex network of transcriptional and post-transcriptional regulatory systems was identified to control expression of these virulence factors and important metabolic functions. In particular, the central carbon metabolism (glycolysis, TCA cycle) and associated amino acid and nucleoside catabolism were found to be co-regulated with expression of Yersinia virulence functions in response to temperature and nutrient availability. To gain a deeper insight into the host-adapted metabolism of Yersinia, the full spectrum of metabolic changes in response to the different virulence associated conditions (changes of temperature, nutrients, oxygen availability) will be elucidated using metabolome, fluxome, transcriptional and 13C-isotopologue profiling techniques. Additionally the molecular mechanisms mediating fine-tuned coregulation of metabolic and virulence genes over the course of the infection will be elucidated. Subsequently, expression and role of the identified host-adapted virulence pathways for pathogenesis will be evaluated in an established mouse infection model. Gained knowledge about crucial host-adapted metabolic pathways of an extracellular fast growing intestinal pathogen may lead to the identification of new targets for novel anti-infective compounds.

肠道病原体假结核耶尔森氏菌在肠道的初始定植以及随后渗透肠上皮层需要一组特殊的早期毒力基因的表达，而在上皮下组织和器官中的持续存在和增殖需要其他致病因子的合成，例如抗吞噬细胞 Yop 蛋白。确定了转录和转录后调节系统的复杂网络来控制这些毒力因子和重要代谢功能的表达。特别是，中心碳代谢（糖酵解、TCA 循环）和相关的氨基酸和核苷分解代谢被发现与耶尔森氏菌毒力功能的表达共同调节，以响应温度和营养物质的利用。为了更深入地了解耶尔森氏菌适应宿主的代谢，将使用代谢组、通量组、转录和 13C 同位素谱分析技术来阐明响应不同毒力相关条件（温度、营养物质、氧气可用性的变化）的全方位代谢变化。此外，还将阐明在感染过程中介导代谢和毒力基因微调共调节的分子机制。随后，将在已建立的小鼠感染模型中评估已确定的宿主适应毒力途径在发病机制中的表达和作用。了解细胞外快速生长的肠道病原体的关键宿主适应代谢途径可能有助于识别新型抗感染化合物的新靶点。