Staphylococcus aureus RNA turnover properties

描述（由申请人提供）：金黄色葡萄球菌是医院和社区获得性感染的主要原因。该生物将其致病能力归功于一系列毒力因子和抗生素耐药性决定因素的产生，以及其对环境挑战的适应性。我们的长期目标是明确控制金黄色葡萄球菌致病性的调控机制。传统上，金黄色葡萄球菌毒力因子的表达被认为在转录物合成水平上受到调控。这一提议的具体假设是金黄色葡萄球菌通过调节这些因子的mRNA周转来调节这些因子。这一假设基于以下观察结果：1)我们已经证明葡萄球菌附属调节剂（sarA）以一种与蛋白质产生负相关的方式稳定毒力因子转录物，2)我们的初步数据表明，金黄色葡萄球菌应激反应的诱导导致mRNA转换的全局改变，3)我们已经证明mRNA衰变的改变与蛋白质产生的变化相关。4)在其他细菌病原体中，mRNA周转的调节是调节蛋白质产生的常见机制。具体目标是：1。表征影响对数期金黄色葡萄球菌mRNA周转的因素。我们认为正常的RNA转换机制功能可以根据内源性和外源性线索而改变。作为确定这些功能如何改变的先决条件，了解天然RNA转换的主要成分至关重要。2. 表征调节mRNA稳定性对蛋白质生产的影响。我们将评估应激介导的mRNA稳定性变化对毒力因子蛋白生产的功能意义。3. 确定瞬时调节mRNA转换的因素。小的非编码RNA分子（sRNAs）和RNA结合蛋白影响细菌mRNA的周转和翻译。我们已经确定金黄色葡萄球菌以生长阶段和/或应激依赖的方式产生139种srna样分子。我们将描述这些分子对金黄色葡萄球菌mRNA周转和蛋白质生产的影响。此外，我们将确定额外的反式作用因子，瞬时改变金黄色葡萄球菌毒力因子mRNA的周转。金黄色葡萄球菌是医院和社区获得性感染的主要原因。本提案的目标是研究生物体调节其毒力因子库并引起疾病的机制。明确这些机制有望为金黄色葡萄球菌感染的治疗干预提供新的策略。

DESCRIPTION (provided by applicant): Staphylococcus aureus is a leading cause of nosocomial and community acquired infections. The organism owes its ability to cause disease to the production of a repertoire of virulence factors and antibiotic resistance determinants, as well as its adaptability to environmental challenges. Our long- term goal is to define the regulatory mechanisms controlling S. aureus pathogenicity. Classically, S. aureus virulence factor expression has been considered to be regulated at the level of transcript synthesis. The specific hypothesis of this proposal is that S. aureus regulates these factors by modulating their mRNA turnover. This hypothesis is based on the following observations: 1) we have shown that the staphylococcal accessory regulator (sarA) stabilizes virulence factor transcripts in a manner that inversely correlates with protein production, 2) our preliminary data indicates that induction of S. aureus stress responses cause global alterations in mRNA turnover, 3) we have shown that alterations in mRNA decay correlate with changes protein production. 4) Modulation of mRNA turnover is a common mechanism of regulating protein production in other bacterial pathogens. The specific aims are to: 1. Characterize factors that influence log-phase S. aureus mRNA turnover. We believe that the normal RNA turnover machinery functions can be altered in response to endogenous and exogenous cues. As a prerequisite to determining how these functions are altered, it is crucial to understand the principle components involved in native RNA turnover. 2. Characterize the effects of modulating mRNA stability on protein production. We will assess the functional significance of stress mediated changes in mRNA stability on virulence factor protein production. 3. Identify factors that transiently modulate mRNA turnover. Small non-coding RNA molecules (sRNAs) and RNA binding proteins influence bacterial mRNA turnover and translation. We have determined that S. aureus produces 139 sRNA-like molecules in a growth phase- and/or stress- dependent manner. We will characterize the effects of these molecules on S. aureus mRNA turnover and protein production. Moreover, we will identify additional trans-acting factors that transiently alter S. aureus virulence factor mRNA turnover. Staphylococcus aureus is a leading cause of hospital and community acquired infections. The goal of this proposal is to investigate the mechanism(s) by which the organism, regulates its repertoire of virulence factors and causes disease. Defining these mechanisms is expected to provide novel strategies for therapeutic intervention of S. aureus infections.