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，GAS）可引起各种人类感染，包括皮肤、咽喉、深部组织甚至血液。虽然这些位点富含肽和蛋白质，但这种多营养缺陷型生物体所必需的游离氨基酸并不丰富。对这种自然环境的适应性反应的分子细节还没有完全探索。因此，需要在调控网络的水平上理解这种反应，该网络将基本代谢过程与毒力基因表达联系起来，并使生物体能够以动态的方式利用富含蛋白质的宿主环境。基于近年来GAS基因组学研究的进展，本研究拟（i）利用DNA微阵列技术，在全基因组水平上确定GAS氨基酸饥饿反应的幅度。这种方法将允许在实验室培养基中以及在模拟或构成全面水平的体内情况的条件下描述严格（RelA+）和松弛菌株（RelA-）的氨基酸饥饿反应。 要链接的严格响应CodY，多效性的转录抑制剂，感觉细胞的营养状态的活动，本研究提出（ii）确定的目标基因的CodY和他们的转录模式作为一个功能的relA确定的鸟苷多磷酸水平。虽然这种方法将使营养应激的反应，以理解在转录水平上的调控的响应基因，本研究的第三个目的提出（iii）确定全球mRNA降解模式在亚基因，基因和操纵子水平，并探讨分子机制参与改变mRNA的半衰期。这将提供有关转录本稳定性如何受环境条件影响的信息。总之，这项研究应该导致一个全面的网络的适应性反应的一个关键的环境条件下，气体可能会遇到与他们的主机。这些知识将有助于了解发病机制，甚至可能导致新的方法来治疗或预防链球菌感染。