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

• 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
• 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

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）：将基因表达限制到细菌生长周期的特定阶段被称为生长阶段调节。对于病原体，通常假定它反映了对动态宿主环境的响应时期的时空适应性。但是，建立此链接需要识别特定的监管元素，其层次关系以及监管网络在体内是否以相似的模式做出反应。由于几乎所有公认的毒力因素的调节都涉及生长阶段 组成部分，这个问题已成为理解由化脓性链球菌链球菌引起的无数和多样性疾病的重要概念。最近的工作已将碳分解代谢物调节（CCR）作为链球菌生长阶段调节的重要组成部分，对毒力基因表达的作用与存在或不存在特定生长底物。这表明底物的可用性是一种主要提示，用于区分感染的特定阶段和/或不同宿主组织之间营养信号的变化可能会促进转录组行为以促进不同的疾病表现。然而，特定的底物感知到CCR的任何调节剂如何在时间和隔室特异性模式中对链球菌转录组的控制行为进行控制，这是该提议的主题。 CCR调节剂称为碳分解代谢物蛋白A（CCPA）对促链球菌中毒力因子基因的时间调节做出了重要贡献。一个主要的问题是，这个单个调节剂如何相对于时间来协调基因表达的多种模式。 CCPA途径在低的G+C型公司中是高度保守的，优雅的研究揭示了CCPA活性如何由多个共同因素调节的结构性基础。但是，在任何细菌中都没有对整合所有这些调节元素的全球调节模式的全面分析。该提案的目的是利用CCPA生物化学的了解，以及链球菌CCPA（SPCCPA）的可能独特特性，对软组织感染中的链球菌碳水化链球菌代谢的全面检查，以及用于在组织中使用的能量生长途径的分析，以探测组织的生长，以探测探针的增长，以探测探针的增长，以探测探针的相关性。