CATABOLITE REPRESSION CONTROLS VIRULENCE IN STREPTOCOCCUS PYOGENES

摘要 将基因表达限制在细菌生长周期的特定阶段称为生长。 阶段调节。对于病原体，它通常被认为反映了在 对动态主机环境的响应。但是，建立此链接需要确定特定的 监管要素及其层级关系，以及监管网络是否在 在体内也有类似的模式。由于对其几乎所有公认的毒力因素的监管都涉及到 阶段组成，这个问题已经成为理解无数和 由人类重要病原体化脓性链球菌引起的多种疾病。最近的工作有 化脓性链球菌生长阶段的重要组成部分--隐含碳分解代谢调控 调节，功能是将毒力基因的表达与是否存在特定的 生长基质。这表明底物的可用性是用于区分 感染的特定阶段和/或不同宿主组织之间营养信号的差异可能 推动转录组行为以促进不同的疾病表现。然而，特定的底物 CCR调控因子对化脓性链球菌转录组的调控作用 时间和舱室特定的模式没有得到很好的理解，这是本提案的主题。一个CCR 被称为碳分解代谢蛋白A(CCPA)的调节因子在时间上做出了重要贡献 化脓性链球菌毒力因子基因的调控。一个主要的问题是，这个单一的监管机构如何 与时间相关的协调不同基因表达模式的功能。CCPA途径是 在低G+C中高度保守和优雅的研究揭示了 CCPA活性是如何受多个辅助因素调节的。然而，没有对模式的全面分析。 整合了所有这些监管要素的全球监管已经在任何细菌中进行过。这个 这项建议的目标是利用CCPA生物化学知识以及可能的独特性质 化脓性链球菌CCPA(SpCcpA)，对其碳水化合物代谢的全面检测 在软组织感染和用于组织生长的能量产生途径的分析中， 为了探索生长底物之间的关系，毒力因子表达的时间调控， CCR与发病机制

Abstract 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