CATABOLITE REPRESSION CONTROLS VIRULENCE IN STREPTOCOCCUS PYOGENES

分解代谢物抑制控制化脓性链球菌的毒力

基本信息

批准号：
9174072
负责人：
Michael G. Caparon
金额：
$ 34.2万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174072
关键词：
Acids Bacteria Behavior Behavior Control Biochemical Biochemistry Carbohydrates Carbon Catalogs ChIP-seq Cues DNA Binding Data Data Set Disease Disease Outcome Elements Environment Fermentation Fructose Gene Expression Gene Expression Profile Gene Proteins Genes Glucose-6-Phosphate Goals Growth Homo Human In Vitro Individual Infection Knowledge Life Link Metabolic Metabolism Modality Modeling Mus Muscle Mutation NADP Nutritional Pathogenesis Pathway interactions Pattern Pharyngeal structure Phase Play Production Property Proteins Regulation Regulatory Element Repression Resolution Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Soft Tissue Infections Source Streptococcus Streptococcus pyogenes Subcutaneous Tissue Testing Time Tissues Variant Virulence Virulence Factors Work carbohydrate metabolism combinatorial in vivo insight mutant novel therapeutics pathogen promoter public health relevance response small molecule spatiotemporal subcutaneous sugar transcriptome transcriptome sequencing virtual

项目摘要

DESCRIPTION (provided by applicant): Restriction of gene expression to a specific phase of the bacterial growth cycle is known as growth phase regulation. For pathogens, it is generally assumed to reflect spatio-temporal adaptations made in response to a dynamic host milieu. However, establishing this link requires identification of specific regulatory elements, their hierarchical relationships, and whether the regulatory network responds in a similar pattern in vivo. Since regulation of virtually all of its recognized virulence factors involves a growth phase component, this issue has emerged as an important concept for understanding the myriad and diverse diseases caused by the important human pathogen Streptococcus pyogenes. Recent work has implicated carbon catabolite regulation (CCR) as an important component of S. pyogenes growth phase regulation, functioning to couple expression of virulence genes to the presence or absence of specific growth substrates. This suggests that substrate availability is a major cue used to distinguish between specific stages of the infection and/or that variation in nutritional signals between different host tissues may drive transcriptome behavior to promote different disease presentations. However, the specific substrates sensed and how any regulator of CCR functions to the control behavior of the S. pyogenes transcriptome in time- and compartment-specific patterns is not well understood and is the subject of this proposal. A CCR regulator known as Carbon Catabolite Protein A (CcpA) makes an important contribution to the temporal regulation of virulence factor genes in S. pyogenes. A major question is how this this single regulator functions to coordinate diverse patterns of gene expression with respect to time. The CcpA pathway is highly conserved among the low G+C firmicutes and elegant studies have revealed the structural basis of how CcpA activity is modulated by multiple co-factors. However, no comprehensive analysis of modes of global regulation that integrates all these regulatory elements has been conducted in any bacterium. The goal of this proposal is to leverage knowledge of CcpA biochemistry along with possible unique properties of S. pyogenes CcpA (spCcpA), a comprehensive examination of S. pyogenes carbohydrate metabolism during infection of soft tissue and an analysis of the energy-producing pathways used for growth in tissue, in order to probe the relationship between growth substrates, temporal control of virulence factor expression, CCR and pathogenesis

描述（由申请人提供）：将基因表达限制在细菌生长周期的特定阶段称为生长期调节。对于病原体，通常认为它反映了针对动态宿主环境而做出的时空适应。然而，建立这种联系需要识别特定的调控元件、它们的层次关系，以及调控网络在体内是否以类似的模式做出反应。由于几乎所有公认的毒力因子的调节都涉及生长阶段组成部分，这个问题已成为理解由重要的人类病原体化脓性链球菌引起的多种疾病的重要概念。最近的工作表明碳分解代谢物调节（CCR）是化脓性链球菌生长阶段调节的重要组成部分，其功能是将毒力基因的表达与特定生长底物的存在或不存在结合起来。这表明底物可用性是用于区分感染特定阶段的主要线索和/或不同宿主组织之间营养信号的变化可能驱动转录组行为以促进不同的疾病表现。然而，所感知的特定底物以及 CCR 的任何调节剂如何以时间和区室特异性模式对化脓性链球菌转录组的控制行为发挥作用尚不清楚，也是本提案的主题。称为碳分解代谢蛋白 A (CcpA) 的 CCR 调节因子对化脓性链球菌毒力因子基因的时间调节做出了重要贡献。一个主要问题是这个单一调节器如何发挥作用来协调不同的基因表达模式随时间的变化。 CcpA 途径在低 G+C 厚壁菌门中高度保守，出色的研究揭示了 CcpA 活性如何受多种辅因子调节的结构基础。然而，尚未在任何细菌中对整合所有这些调控元件的全局调控模式进行全面分析。该提案的目标是利用 CcpA 生物化学知识以及化脓性链球菌 CcpA (spCcpA) 可能的独特特性，对软组织感染期间化脓性链球菌碳水化合物代谢进行全面检查，并对所用的能量产生途径进行分析用于组织中的生长，以探讨生长底物、毒力因子表达的时间控制、CCR 和发病机制之间的关系