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

解读 Rgg 在肺炎球菌信号传导、定植和毒力组合中的作用

• 批准号: 10383656
• 负责人: Natalia Luisa Hiller
• 金额: $ 33.51万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-23 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383656
• 关键词: Adhesions; Agonist; Binding; Binding Sites; Biological Assay; Cell physiology; Cells; Chronic; Competence; Complex; Contracts; DNA; DNA-Protein Interaction; Development; Disease; Disease model; EMSA; Enterococcus; Family; Future; Galactose; Genetic; Genetic Transcription; Glycoproteins; Goals; Growth; Immune Evasion; In Vitro; Infection; Knowledge; Lead; Light; Link; Luciferases; Mannose; Maps; Mediating; Microbial Biofilms; Molecular; Molecular Probes; Morbidity - disease rate; Mucous Membrane; Nasopharynx; Nutrient; Order Coleoptera; Peptide Signal Sequences; Peptides; Phenotype; Play; Pneumococcal Colonization; Pneumococcal Infections; Pneumonia; Post-Transcriptional Regulation; Process; Promoter Regions; Proteins; Public Health; Regulation; Reporter; Role; Series; Signal Transduction; Streptococcus; Streptococcus pneumoniae; Synthetic Peptide Libraries; System; Testing; Tissues; Transcriptional Regulation; United States; Virulence; Work; antagonist; antimicrobial; capsule; design; drug development; improved; in vivo; innovation; insight; mortality; mouse model; promoter; receptor; spatiotemporal; therapeutic development; time use; tool

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.

项目概要 该项目的总体目标是增进我们对肺炎球菌定植的了解。 肺炎球菌疾病是美国和全世界发病和死亡的主要原因， 鼻咽部定植是肺炎球菌感染的第一步。虽然很多人都知道 关于与肺炎球菌定植相关的表型和细胞过程，分子 协调这些过程还没有得到很好的理解。我们的初步工作描述了 Rgg144- Shp144 调节肽信号转导系统使我们假设该系统发挥着 在协调肺炎球菌定植中发挥关键作用。在广泛的层面上，我们的工作将提供对 肺炎球菌定植和信号转导系统 Rgg 家族，广泛分布于 链球菌和肠球菌。在特定层面上，我们将确定哪些与殖民相关 表型受 Rgg144 调节，并确定 Rgg144 是否介导这些表型 胶囊的调节（目标 1）。我们将鉴定与肽调节剂相关的特定残基 相互作用以及调节子-DNA 相互作用（目标 2）。我们将揭示 SHP144 衍生的肽，其作用 作为体外和体内的激动剂和拮抗剂，用于操纵系统的基本功能 研究以及未来的药物开发工作（目标 2 和 3）。我们将提供体内 使用两种不同的小鼠表征 Rgg144 在多个组织中随时间的表达和活性 肺炎球菌感染模型（目标 3）。我们的研究结果将共同揭示 Rgg144 的贡献 荚膜的转录调控，增进我们对肺炎球菌定植的理解， 并阐明抗肺炎球菌疗法的发展。这项工作的创新之处在于 通过生成 Rgg144 表达和活性的时空图来研究 Rggs 感染期间。