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

项目摘要 化脓性链球菌，也称为A组链球菌（GAS），是一种革兰氏阳性病原体，其 毒力状态，是负责多种人类疾病，从急性咽炎，脓疱，猩红 发烧和坏死性筋膜炎除了对这些疾病状态的贡献外，细菌还 无症状地殖民高达35%的人口，这种殖民状态仍然是其主要水库， 生存我们的小组已经确定了一个新的群体感应系统在S。化脓性链球菌称为Rgg 2/3 该途径由两个转录调节因子组成，激活因子（Rgg 2）和阻遏因子（Rgg 3）， 由两个短疏水肽信号（SHP）调节。RGG 2/3回路调节一个小的分泌性 Stc蛋白，其诱导增加的生物膜形成和增强的溶菌酶抗性。这两 表型是细菌细胞表面改变的指示，我们最近已经表明， 带正电荷的Stc蛋白分泌到细胞表面，在那里它与表面部分结合， 使表面带更多的正电荷。该建议旨在确认Stc与之结合的表面部分 关联，并确定它们是否因Stc的存在而被宿主检测到。我们 初步数据显示Stc表达导致NFκB活化降低，这导致我们 相信Stc表达细菌将具有定殖优势。小鼠鼻内定植模型 将进行以证实这种定殖优势以及检查体内NFκB反应。成功 该项目的工作将使我们能够探索使用已经确定的破坏Rgg 2/3 QS的治疗方法， 以消除处于殖民状态的细菌。

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.