A quorum-sensing-regulated protein controls cell surface alteration in S. pyogenes

项目总结 化脓性链球菌，又称A组链球菌(GAS)，是一种革兰氏阳性病原菌，在其 毒力状态，是多种人类疾病的罪魁祸首，从急性咽炎、脓疱疮、猩红 发烧和坏死性筋膜炎。除了对这些疾病状态的贡献外，这种细菌还 无症状地殖民高达35%的人口，这种殖民状态仍然是它的主要储备库 生死存亡。本课题组在化脓性链球菌中发现了一种新的群体感应系统，命名为Rgg2/3 由两个转录调节因子、激活因子(Rgg2)和抑制因子(Rgg3)组成的途径 受两个短疏水多肽信号(SHPS)的调节。RGG 2/3电路调节一个小的分泌物 蛋白质，STC，诱导增加生物膜的形成和增强对溶菌酶的抗性。这两个都是 表型表明细菌的细胞表面发生了变化，我们最近发现 带正电荷的STC蛋白被分泌到细胞表面，在那里它与表面部分和 使表面更带正电。这一建议试图确认STC与 关联，并确定它们是否因STC的存在而不被主机检测到。我们 有初步数据显示，STC的表达会导致NFκB的活性降低，这导致我们 相信表达STC的细菌将具有定植优势。小鼠鼻腔定植模型的建立 将进行以确认这一定植优势以及检测体内的核因子κB反应。成功 这个项目的工作将使我们能够探索使用已经确定的治疗方法，按顺序扰乱Rgg2/3 QS 以消灭处于定植状态的细菌。

PROJECT SUMMARY Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is a gram-positive pathogen that, in its virulent state, is responsible for a variety of human diseases ranging from acute pharyngitis, impetigo, scarlet fever, and necrotizing fasciitis. In addition to its contribution to these disease states, the bacterium is also asymptomatically colonizing up to 35% the population, and this colonization state remains its major reservoir for survival. Our group has characterized a novel quorum sensing system in S. pyogenes termed the Rgg2/3 pathway which consists of two transcriptional regulators, an activator (Rgg2) and a repressor (Rgg3) that are modulated by two short hydrophobic peptide signals (SHPs). The Rgg 2/3 circuit regulates a small secreted protein, Stc, that induces increased biofilm formation and enhanced lysozyme resistance. Both of these phenotypes are indicative of alterations to the cell surface of the bacterium, and we have recently shown that the positively-charged Stc protein is secreted to the cell surface where it associates with surface moieties and makes the surface more positively charged. This proposal seeks to confirm the surface moieties with which Stc associates, and determine whether or not they are obscurred from detection by the host by Stc’s presence. We have preliminary data showing that Stc expression leads to decreased activation of NFκB, which leads us to believe the Stc-expressing bacteria will have a colonization advantage. A murine model of intranasal colonization will be carried out to confirm this colonization advantage as well as examine the NFκB response in vivo. Success of this project work will allow us to explore use of already identified therapeutics that disrupt Rgg2/3 QS in order to eliminate bacteria in a colonizing state.