CATABOLITE REPRESSION CONTROLS VIRULENCE IN STREPTOCOCCUS PYOGENES

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阶段调节。对于病原体，它通常被认为是反映时空适应动态主机环境。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，以及调控网络是否在体内以类似的模式响应。由于几乎所有公认的毒力因子的调节都涉及生长阶段， 作为一个重要的组成部分，这个问题已经成为理解由重要的人类病原体化脓性链球菌引起的无数不同疾病的一个重要概念。最近的研究表明，碳分解代谢物调节（CCR）是沙门氏菌的重要组成部分。化脓性链球菌生长期调节，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偶联。这表明底物可用性是用于区分感染的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，特定的底物感测和CCR的任何调节器如何作用于S的控制行为。化脓性链球菌转录组在时间和区室特异性模式中的作用还没有得到很好的理解，这是本提案的主题。一种称为碳分解代谢物蛋白A（CcpA）的CCR调节因子对S.化脓一个主要的问题是，这个单一的调节器是如何发挥作用的，以协调不同的基因表达模式，随着时间的推移。CcpA途径在低G+C厚壁菌门中高度保守，并且优雅的研究已经揭示了CcpA活性如何被多种辅因子调节的结构基础。然而，没有全面的分析模式的全球监管，整合所有这些监管要素已进行任何细菌。本提案的目的是利用CcpA生物化学知识沿着S.化脓性链球菌CcpA（spCcpA），对S.软组织感染过程中化脓性链球菌的碳水化合物代谢和用于组织生长的能量产生途径的分析，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

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