Response of Streptococcus pyogenes to Nutritional Stress

化脓性链球菌对营养应激的反应

• 批准号: 7096084
• 负责人: Joseph J Ferretti
• 金额: $ 29.3万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096084
• 关键词: Streptococcus pyogenes; bacteria infection mechanism; bioinformatics; confocal scanning microscopy; gene expression; guanine nucleotides; host organism interaction; laboratory mouse; messenger RNA; microarray technology; operon; pharyngitis; polymerase chain reaction; skin infection; virulence

DESCRIPTION (provided by applicant): Streptococcus pyogenes (group A streptococcus, GAS) causes various infections of humans including the skin, throat, deep tissue, and even the bloodstream. Although these sites are rich in peptides and proteins, free amino acids, which are essential for this polyauxotrophic organism, are not abundant. The molecular details of the adaptive response to such natural environments are incompletely explored. This response needs to be understood, therefore, at the level of a regulatory network that links basic metabolic processes to virulence gene expression and enables the organism in a dynamic way to take advantage of protein-rich host environments. Based on the advances made in the genomics of GAS in recent years, this study proposes to (i) determine the breadth of the amino acid starvation response of GAS on a genome-wide scale, by global transcription profiling using DNA microarray technology. This approach will allow description of the amino acid starvation response of stringent (RelA+) and relaxed strains (RelA-) in laboratory media as well as in conditions that mimic or constitute in-vivo situations at a comprehensive level. To link the stringent response to the activity of CodY, a pleiotropic transcriptional repressor that senses the nutritional state of the cell, this study proposes to (ii) identify the target genes of CodY and their transcription pattern as a function of the relA-determined guanosine polyphosphate level. While this approach will enable the response to nutritional stress to be understood at the level of transcriptional regulation of the responsive genes, the third aim of this study proposes to (iii) determine global mRNA degradation patterns at the sub-genic, genic and operonic levels and explore molecular mechanisms involved in the alteration of mRNA half-lives. This will provide information about how transcript stability is influenced by environmental conditions. Taken together, this research should result in a comprehensive network of adaptive responses to a key environmental condition that GAS may encounter in association with their host. This knowledge will help understand pathogenetic mechanisms and may even lead to new approaches for treatment or prevention of streptococcal infections.

描述（由申请人提供）：化脓性链球菌（A组链球菌，气体）会引起人类的各种感染，包括皮肤，喉咙，深层组织，甚至是血液。尽管这些位点富含肽和蛋白质，但对这种多养生生物至关重要的游离氨基酸并不丰富。未完全探讨了对这种自然环境的自适应反应的分子细节。因此，需要在调节网络的级别上理解这种反应，该响应将基本代谢过程与毒力基因表达联系起来，并以动态的方式使生物体利用富含蛋白质富含蛋白质的宿主环境。基于近年来气体基因组学的进步，这项研究建议（i）通过使用DNA微阵列技术进行全球转录分析，确定气体在全基因组范围内的氨基酸饥饿反应的广度。这种方法将允许描述实验室媒体中严格（RELA+）和放松菌株（Rela-）的氨基酸饥饿反应，以及在综合级别模仿或构成体内情况的条件下。 为了将严格的反应与Cody的活性联系起来，Cody是一种感知细胞营养状态的多效转录阻遏物，本研究建议（ii）识别Cody的靶基因及其转录模式作为Rela确定的鸟氨酸多磷酸盐水平的函数。尽管这种方法将使对营养应激的反应在响应基因的转录调控水平上得到理解，但本研究的第三个目的建议（iii）确定（iii）确定在亚基因，基因和操作水平上的全球mRNA降解模式，并探索涉及mRNA半流量变化的分子机制。这将提供有关转录稳定性如何受环境条件影响的信息。综上所述，这项研究应导致对与宿主相关的气体可能遇到的关键环境状况的全面自适应响应网络。这些知识将有助于理解致病机制，甚至可能导致用于治疗或预防链球菌感染的新方法。