PRD-Containing Virulence Regulators of Pathogenic Streptococci

描述（由申请人提供）：细菌病原体必须适应宿主体内可用的营养物质，因此它们的代谢与毒力有关。我们想了解G+病原体对可用碳水化合物调节毒力的机制。GAS是引起一系列疾病的重要病原体，宿主的生存依赖于糖的摄取。PTS是一个结合糖转运和信号转导的保守磷接力。Mga调节因子影响GAS的毒力和糖利用基因。我们已经证明Mga在PTS调控域（PRD）内被磷酸化，这改变了Mga在GAS中的活性和毒力。此外，在GAS和其他致病性链球菌中也发现了同源调节因子。我们认为Mga代表了一个含有prd的毒力调节因子（PCVR）家族，它允许糖代谢影响疾病过程。这一更新将继续我们对Mga作为原型PCVR的研究，同时扩大我们的范围，包括来自致病性链球菌的潜在PCVR。我们提出以下目标：1)进一步确定Mga的功能域，并确定其在其他致病性链球菌PCVRs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)利用n-seq绘制GAS中Mga的全基因组遗传相互作用图谱；4)检测GAS感染期间PTS信号对Mga和潜在ralp的影响。加深我们对PCVRs的理解将在G+细菌发病机制领域产生广泛的影响，并有望产生新的策略来治疗由这些病原体引起的严重感染。

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.