PRD-Containing Virulence Regulators of Pathogenic Streptococci

描述(申请人提供)：细菌病原体必须适应其宿主中可用的营养物质，因此它们将新陈代谢与毒力联系在一起。我们想要了解G+病原体调节毒力以响应可用碳水化合物的机制。GAS是一种重要的病原体，会导致一系列疾病，并依赖于糖的摄取来维持宿主的生存。PTS是一种保守的磷酸传递信号转导系统，MGA调节因子同时影响GAS中的毒力基因和糖利用基因。我们已经证明MGA在PTS调节域(PRD)内被磷酸化，从而改变MGA在GAS中的活性和毒力。此外，在GAS和其他致病链球菌中也发现了相应的调节剂。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。这次更新将继续我们对MGA作为PCVR原型的研究，同时扩大我们的范围，包括来自致病性链球菌的潜在PCVR。我们建议的目标如下：1)进一步定义MGA的功能结构域，并在致病链球菌的其他PCVR中建立它们的保守性；2)描述PTS成分和糖在GAS中通过MGA和潜在的其他RALP信号传递的作用；3)使用TN-SEQ定位MGA在GAS中的全基因组遗传相互作用；4)检测PTS信号在GAS感染过程中对MGA和潜在的RALP的影响。提高我们对PCVRs的认识有可能在G+细菌发病机制领域产生广泛影响，并有望导致治疗由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.