PRD-Containing Virulence Regulators of Pathogenic Streptococci

描述（申请人提供）：细菌病原体必须适应宿主体内的可用营养物质，因此它们将代谢与毒力联系起来。我们希望了解G+病原体调节毒力以响应可用碳水化合物的机制。GAS是引起一系列疾病的重要病原体，并且依赖于宿主存活的糖摄取。PTS是一个保守的糖转运和信号转导的磷酸化介导蛋白，Mga调节子影响GAS的毒力和糖利用基因。我们已经表明，Mga是磷酸化的PTS调节结构域（PRD），改变Mga的活性和毒性在GAS。此外，在GAS和其他致病性链球菌中发现了同源调节子。我们认为Mga代表了一个含有PRD的毒力调节因子（PCVR）家族，该家族允许糖代谢影响疾病过程。此次更新将继续我们对Mga作为原型PCVR的研究，同时将我们的范围扩大到包括来自致病性链球菌的潜在PCVR。我们提出以下目标：1）进一步定义Mga的功能结构域，并建立它们在来自致病性链球菌的其他PCVR中的保守性; 2）描述PTS组分和糖在GAS中通过Mga和潜在的其他RALP进行信号传导的作用; 3）使用Tn-seq绘制GAS中Mga的全基因组遗传相互作用; 4）检查GAS感染期间PTS信号传导对Mga和潜在的RALP的影响。推进我们对PCVRs的理解在G+细菌发病机制领域具有广泛的影响潜力，并有望导致治疗这些病原体引起的严重感染的新策略。

DESCRIPTION (provided by applicant): Bacterial pathogens must adapt to available nutrients in their host, so they have linked metabolism with virulence. We want to understand the mechanisms by which G+ pathogens regulate virulence in response to available carbohydrates. GAS is a significant pathogen causing an array of diseases and depends upon sugar uptake for host survival. The PTS is a conserved phosphorelay coupling sugar transport and signal transduction.The Mga regulator influences both virulence and sugar utilization genes in GAS. We've shown that Mga is phosphorylated within PTS regulatory domains (PRD) that alter Mga activity and virulence in GAS. Furthermore, homologous regulators are found in GAS and other pathogenic streptococci. We propose that Mga represents a family of PRD-containing virulence regulators (PCVR) that allows sugar metabolism to influence the disease process. This renewal will continue our studies on Mga as the archetype PCVR, while expanding our scope to include potential PCVR from pathogenic streptococci. We propose the following aims: 1) Further define functional domains of Mga and establish their conservation in other PCVRs from pathogenic streptococci; 2) Delineate the role of PTS components and sugars for signaling through Mga and potentially other RALPs in GAS; 3) Map the genome-wide genetic interactions of Mga in GAS using Tn-seq; 4) Examine the impact of PTS signaling on Mga and potentially RALPs during GAS infection. Advancing our understanding of PCVRs has potential for broad impact in the field of G+ bacterial pathogenesis and will hopefully lead to novel strategies to treat severe infections caused by these pathogens.