Elucidating Rgg-mediated quorum sensing networks in Streptococcus pneumoniae and their contributions in pathogenesis

摘要 群体感应(QS)，或细菌通过细胞间化学信号进行通信，是许多人(如果)共同的过程 不是大多数)细菌种类；然而，目前还不清楚QS信号通路如何在许多临床上对毒力起作用 重要的病原体。费德勒实验室帮助确定了被称为RGG的转录调控家族的特征 蛋白质，作为QS的介体。我们和其他人已经证明了RGG蛋白在多个物种中的重要性 链球菌能调节基因的表达，从而增强其定植和感染宿主的能力。RGG蛋白 已知的是调节1)控制毒力的重要基因；2)促进对 溶菌酶，一种宿主产生的抗菌酶；3)刺激生物膜的形成，或保护性细菌 社区；4)启动从环境中提取DNA的自然能力的发展；5) 促进与上皮细胞的黏附能力。RGG蛋白在临床致病生活方式中的作用 重要的病原体肺炎链球菌尚未被研究，但已发表的基因组水平的突变研究表明 这种生物体中的RGG蛋白在体内感染动物模型中起着关键作用。我们已经构建了等位基因突变体 每个RGG蛋白在体内都很重要，并进行了转录分析以确定RGG-下的基因靶点 监管。我们的分析揭示了肺炎球菌中受RGG蛋白SP_0141调控的18个基因靶点 囊化菌株TIGR4(血清4型)。我们正在测试感兴趣的基因靶点，以便了解 RGG介导的QS及其在毒力中的作用然后，我们将探索使用QS来调节 发病机制中存在免疫监视。理解QS调控下的分子网络和 在宿主中使用QS的优势将支持将QS作为一种有效的策略进行调制的可能性 对抗病原体。

Abstract Quorum Sensing (QS), or bacterial communication by intercellular chemical signaling, is a process common to many (if not most) bacterial species; yet, it is unclear how QS signaling pathways contribute to virulence in many clinically significant pathogens. The Federle lab has helped to characterize a family of transcriptional regulators, known as Rgg proteins, as mediators of QS. We and others have shown the importance of Rgg proteins in multiple species of streptococci in regulating expression of genes that may enhance their ability to colonize and infect the host. Rgg proteins are known to regulate genes important for 1) controlling virulence; 2) promoting the development of resistance to lysozyme, a host-produced antimicrobial enzyme; 3) stimulating the formation of biofilms, or protective bacterial communities; 4) initiating the development of natural competence to take up DNA from the environment; and 5) promoting the ability to adhere to epithelial cells. The role of the Rgg proteins in the pathogenic lifestyle of the clinically significant pathogen S. pneumoniae has yet to be investigated, but published genome-level mutagenesis studies indicate Rgg proteins in this organism are critical in in vivo animal models of infection. We have constructed isogenic mutants for each Rgg protein important in vivo and have performed transcriptomic analysis to identify gene targets under Rgg- regulation. Our analysis has revealed 18 gene targets under regulation by the Rgg protein SP_0141 in the pneumococcal encapsulated strain TIGR4 (serotype 4). We are in the process of testing gene targets of interest in order to understand Rgg-mediated QS and its role in virulence. We will then explore the consequences of using QS to regulate mechanisms of pathogenesis in the presence of immune surveillance. Understanding the molecular networks under QS regulation and the advantage of using QS in the host will provide support for the possibility of modulating QS as an effective strategy for combatting pathogens.