Effect of iron availability on Staphyloccocus aureus exoprotein production.

描述(申请人提供)：美国医院每年有120多万名患者感染金黄色葡萄球菌。金黄色葡萄球菌作为病原体的巨大成功在一定程度上是由于大量外源蛋白的表达。不同寄主环境对金黄色葡萄球菌外源蛋白全球表达的影响尚不完全清楚。金黄色葡萄球菌在体内可能感觉到的一个环境线索是铁可获得性的波动。这一应用的中心假设是金黄色葡萄球菌在感染期间感知铁可获得性的变化，以协调特定的外蛋白表达谱，从而促进细菌生存。这一假说得到了这里提供的初步数据的支持，这些数据表明，金黄色葡萄球菌对细胞毒素和免疫调节蛋白的表达做出了差异协调，以响应铁可获得性的变化。这项应用的目的是确定金黄色葡萄球菌的分子机制，我们将使用动物模型和体外原代培养感染模型相结合的方法来研究金黄色葡萄球菌超抗原样外毒素(SSL)在金黄色葡萄球菌与宿主相互作用中的作用。目的二确定负责外源蛋白铁依赖调控的调控系统(S)，并阐明该系统(S)在金黄色葡萄球菌致病中的作用。我们将应用DNA结合分析、转座子筛选和微阵列来促进对负责金黄色葡萄球菌外源蛋白铁依赖表达的分子(S)的鉴定和表征。此外，我们还将确定铁敏感系统(S)在金黄色葡萄球菌致病过程中的作用以及铁调控的外源蛋白在体内的表达。 相关性：这项拟议的研究将调查金黄色葡萄球菌如何感知宿主环境来调节外源蛋白的表达，以及这些外源蛋白在金黄色葡萄球菌发病中的作用。了解金黄色葡萄球菌在感染过程中如何协调毒力因子的表达，以及这些因子对宿主的影响，可能会为产生针对这种重要人类病原体的新疗法提供靶点。

DESCRIPTION (provided by applicant): Staphylococcus aureus infects more than 1.2 million patients per year in U.S. hospitals. The tremendous success of S. aureus as a pathogen is in part due to the expression of an arsenal of exoproteins. The effects of different host environments on the global expression of S. aureus exoproteins are not completely understood. One environmental cue that S. aureus likely senses in vivo is fluctuations in iron availability. The central hypothesis of this application is that S. aureus senses changes in iron availability during infection to coordinate a specific exoprotein expression profile that facilitates bacterial survival. This hypothesis is supported by the preliminary data presented here, which demonstrate that S. aureus differentially coordinates the expression of cytotoxins and immunomodulatory proteins in response to changes in iron availability. The goals of this application are to determine the molecular mechanisms by which S. aureus sensically, we will investigate the role of Staphylococcal Superantigen-like exotoxins (Ssl) in S. aureus-host interactions using a combination of animal models and ex vivo primary culture models of infection. Aim two is designed to identify the regulatory system(s) responsible for iron-dependent regulation of exoproteins and to delineate the role of this system(s) in S. aureus pathogenesis. We will apply a combination of DNA binding assays, transposon screens, and microarrays to facilitate the identification and characterization of the molecule(s) responsible for the iron-dependent expression of S. aureus exoproteins. Furthermore, we will determine the contribution of the iron-sensing system(s) to S. aureus pathogenesis and to the in vivo expression of iron-regulated exoproteins. RELEVANCE: The proposed research will investigate how S. aureus senses host environments to regulate the expression of exoproteins and the function of these exoproteins in S. aureus pathogenesis. Understanding how S. aureus coordinates the expression of virulence factors during infection and the effects of these factors on the host may uncover targets for the generation of novel therapeutics against this important human pathogen.