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，通常认为它反映了对动态宿主环境的时空适应。然而，建立这种联系需要确定特定的调节元件，它们的等级关系，以及调节网络是否在体内以类似的模式做出反应。因为几乎所有已知的毒力因子的调节都涉及到一个生长阶段 这一问题已经成为了解由人类重要病原体化脓性链球菌引起的无数不同疾病的重要概念。最近的工作表明，碳分解代谢调节(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联系起来。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的营养信号的差异可能驱动转录组行为以促进不同的疾病表现的主要线索。然而，所感知的特定底物以及CCR的任何调节因子如何在时间和隔室特定的模式中对化脓性链球菌转录组的控制行为起作用还不是很清楚，这是本提案的主题。一个被称为碳分解代谢蛋白A(CCPA)的CCR调节因子在化脓性链球菌毒力因子基因的时间调控中做出了重要贡献。一个主要的问题是，这个单一的调控因子如何发挥作用，以协调与时间相关的基因表达的不同模式。CCPA途径在低G+C组中是高度保守的，优雅的研究揭示了CCPA活性如何受到多个辅助因子调节的结构基础。然而，还没有对整合了所有这些调控因素的全球调控模式进行全面分析，没有对任何细菌进行过。这项建议的目的是利用ccpa生化知识和化脓性链球菌(SpccpA)可能的独特性质，全面检查化脓性链球菌在软组织感染过程中的碳水化合物代谢，并分析组织中用于生长的能量产生途径，以探索生长底物、毒力因子表达的时间控制、ccr与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