Deciphering the Role of Rgg in the Pneumococcal Signaling, Colonization and Virulence Portfolio

项目摘要 这个项目的总体目标是促进我们对肺炎球菌定植的理解。 肺炎球菌疾病是美国和世界范围内发病率和死亡率的主要原因， 而鼻咽定植是肺炎球菌感染的第一步。虽然我们知道的很多 关于与肺炎球菌定植相关的表型和细胞过程，这些分子 协调这些过程还没有得到很好的理解。我们的初步工作是对Rgg144- Shp144调节因子-多肽信号转导系统使我们假设该系统发挥了 在协调肺炎球菌定植方面的关键作用。在更广泛的层面上，我们的工作将提供对 肺炎球菌定植和RGG信号转导系统家族，广泛分布于 链球菌和肠球菌。在一个特定的层面上，我们将确定哪一种殖民与 表型由Rgg144调节，并确定Rgg144是否通过 胶囊的调节(目标1)。我们将鉴定与多肽调节剂相关的特定残基 相互作用和与调节剂-DNA相互作用(目标2)。我们将揭示SHP144衍生肽的作用 作为体外和体内的激动剂和拮抗剂，用于在基本功能上操纵系统 研究以及未来的药物开发努力(目标2和3)。我们将在体内提供一种 利用两种不同的小鼠研究Rgg144在多个组织中的表达和活性随时间的变化 肺炎球菌感染模型(目标3)。总之，我们的发现将揭示Rgg144的贡献 为了对衣壳进行转录调控，增进我们对肺炎球菌定植的理解， 并为抗肺炎球菌疗法的发展提供了线索。这项工作的创新之处在于它 通过生成Rgg144表达和活性的时空图探讨Rggs的研究 在感染期间。

Project Summary The overall goal of this project is to advance our understanding of pneumococcal colonization. Pneumococcal diseases are major causes of morbidity and mortality in the United States and worldwide, and colonization of the nasopharynx is the first step for pneumococcal infections. While much is known about phenotypes and cellular processes associated with pneumococcal colonization, the molecules coordinating these processes are not well understood. Our preliminary work characterizing the Rgg144- Shp144 regulator-peptide signal transduction system has lead us to hypothesize that this system plays a pivotal role in orchestrating pneumococcal colonization. At a broad level, our work will provide insight into pneumococcal colonization and the Rgg family of signal transduction systems, widely distributed in streptococci and enterococci. At a specific level, we will determine which colonization-associated phenotypes are regulated by Rgg144 and establish whether Rgg144 mediates these phenotypes via regulation of the capsule (Aim 1). We will to identify specific residues associated with peptide-regulator interactions and with regulator-DNA interactions (Aim 2). We will reveal SHP144-derived peptides that act as agonists and antagonists in vitro and in vivo, for use in manipulating the system in basic functional studies as well as future drug development efforts (Aim 2 and 3). We will provide an in vivo characterization of Rgg144 expression and activity in multiple tissues over time using two different murine models of pneumococcal infection (Aim 3). Together, our findings will uncover the contribution of Rgg144 to transcriptional regulation of the capsule, advance our understanding of pneumococcal colonization, and shed light on the development of anti-pneumococcal therapies. The work is innovative in that it approaches the study of Rggs by generating a spatio-temporal map of Rgg144 expression and activity during infection.