Innate Immunity and Bacterial Quorum Sensing

先天免疫和细菌群体感应

• 批准号: 6914673
• 负责人: Hattie D. Gresham
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914673
• 关键词: Staphylococcus aureus; Staphylococcus epidermidis; Staphylococcus infection; bacterial cytopathogenic effect; carboxylic ester hydrolases; clinical research; enzyme activity; free radical oxygen; genetically modified animals; host organism interaction; human tissue; immunity; laboratory mouse; lactones; mass spectrometry; oxidoreductase; peroxidases; phagocytes; quorum sensing; virulence

DESCRIPTION (provided by applicant): Quorum sensing is a cell-to-cell communication system that permits members of a bacterial population to coordinate their behavior dependent on cell density. The mediators of quorum sensing are small, diffusible pheromones or autoinducers that signal gene expression programs at a sufficient bacterial density. The list of bacterial pathogens that use this method of communication to regulate host colonization and virulence is expanding and includes some of the most common pathogens of humans. We hypothesized that several mammalian effectors contribute to innate immunity by inhibiting pathogenic bacterial communication via "quorum quenching." In preliminary data we show that phagocyte-derived reactive oxygen and nitrogen intermediates (ROI and RNI) target a virulence-inducing peptide of the medically important human pathogen Staphylococcus aureus as an innate defense mechanism of the host. In addition, enzymes in blood and epithelial cells that cleave lactone bonds that are present in these autoinducers could inhibit quorum sensing-dependent virulence. To test this hypothesis, we will pursue the following specific aims: 1) To determine the contribution of phagocyte-derived ROI and RNI to host defense against infection with quorum sensing-sufficient and -deficient strains of S. aureus and S. epidermidis and the ability of ROI and RNI to functionally inactivate the virulence pheromones secreted by these pathogens; 2) To determine the ROI- and RNI-mediated modifications of these virulence pheromones by mass spectrometry in vitro and their biologic significance in vivo; and 3) To determine if non-phagocyte innate effectors inhibit quorum sensing-dependent virulence. These will include the paraoxonase enzyme family (thiolactonases) and the epithelial cell-expressed Nox/Duox enzymes (oxidases and peroxidases). Understanding the contribution of these innate effectors to quorum quenching and how pathogens avoid it could augment drug design that targets virulence pheromones for inactivation.

描述（由申请人提供）：法定感应是一种细胞到细胞通信系统，允许细菌种群的成员协调其行为取决于细胞密度。法定感应的介体是小的，可扩散的信息素或自动诱导剂，它们以足够的细菌密度为基因表达程序。使用这种传播方法来调节宿主定植和毒力的细菌病原体列表正在扩大，其中包括一些人类的一些最常见的病原体。我们假设几个哺乳动物效应子通过“法定淬火”抑制致病细菌的通信来促进先天免疫。在初步数据中，我们表明，吞噬细胞衍生的活性氧和氮中间体（ROI和RNI）的目标是医学上重要的人类病原体葡萄球菌金黄色葡萄球菌作为宿主先天防御机制的毒力诱导肽。另外，这些自动诱导剂中存在的裂解内酯键的血液和上皮细胞中的酶可以抑制群体感应依赖性的毒力。为了检验这一假设，我们将追求以下具体目的：1）确定吞噬细胞衍生的ROI和RNI的贡献，以征服s. s. o. s. o. s. opedsing and S. o. opedsing and S. eureus and S. epistermidis以及ROI和RNI的能力和RNI在功能上均通过这些病毒式pheremented Pherogence pheromented Pheromented pherosement pherogesections的贡献； 2）确定通过质谱法及其在体内的生物学意义，确定这些毒力信息素的ROI和RNI介导的修饰； 3）确定非晶状细胞先天效应子是否抑制了群体感应依赖性的毒力。这些将包括副氧酶家族（硫代乳激酶）和上皮细胞表达的NOX/DUOX酶（氧化酶和过氧化物酶）。了解这些先天效应子对法规淬火的贡献以及病原体如何避免它可以增强靶向毒力信息素的药物设计。