Role of the saeR/S gene regulatory system in S. aureus pathogenesis

性状（由申请人提供）：金黄色葡萄球菌（S.金黄色葡萄球菌）是世界范围内人类感染的主要原因，并引起严重程度从轻度到危及生命的多种疾病。S.金黄色葡萄球菌引起疾病的部分原因是其破坏先天免疫系统的能力。最近的研究表明S.金黄色葡萄球菌逃避人多形核白细胞（PMN或嗜中性粒细胞）的杀伤。然而，关于病原体如何检测先天免疫系统的组成部分以在宿主内做出反应和存活，人们知之甚少。因此，本研究的长期目标是更好地了解S。金黄色葡萄球菌致病性。具体的假设是saeR/S促进S逃避宿主的先天防御。金黄色葡萄球菌，因此对发病机制很重要。这一假设基于以下几个关键观察结果：1）saeR/S影响毒力因子的表达; 2）saeR/S似乎在整合细胞密度信号与环境刺激的线索中发挥作用; 3）在5种S强毒株中，saeR/S在与人PMN相互作用期间高度上调。金黄色。基于这些观察（来自我们的小组和其他人），本建议的重点是确定S中saeR/S的功能。金黄色葡萄球菌发病机制这将通过针对两个具体目标的研究来实现。第一个目标是利用S.金黄色葡萄球菌菌株MW 2（脉冲场型USA 400）。这一目标将通过创建一个saeR/S缺失突变体和研究PMN吞噬作用，ROS的产生，和杀菌活性对saeR/S突变体和野生型菌株来实现。此外，该目的将确定在野生型S中是否诱导saeR/S。金黄色葡萄球菌的特异性PMN成分。寡核苷酸芯片也将被用来获得一个全面的分析saeR/S的影响，S。金黄色葡萄球菌第二个目标将决定saeR/S对S是否重要。金黄色葡萄球菌毒力的小鼠模型。金黄色葡萄球菌感染。小鼠模型将由软组织和菌血症组成，并将通过感染组织的组织病理学进行分析。总之，我们预期这些研究将为了解saeR/S在S.金黄色葡萄球菌发病机制也许更重要的是，拟议的研究应该确定致病战略使用的S。金黄色葡萄球菌引发感染。

DESCRIPTION (provided by applicant): Staphylococcus aureus (S. aureus) is a leading cause of human infections worldwide and causes a variety of diseases ranging in severity from mild to life-threatening. The ability of S. aureus to cause disease is based in part on its ability to subvert the innate immune system. Recent studies suggest S. aureus evades killing by human polymorphonuclear leukocytes (PMNs or neutrophils). However, relatively little is known about how pathogens detect components of the innate immune system to respond and survive within the host. Therefore, the long term goal of this study is to gain a better understanding of S. aureus pathogenesis. The specific hypothesis is that saeR/S facilitates evasion of innate host defenses by S. aureus and is therefore important for pathogenesis. This hypothesis is based on a few key observations: 1) saeR/S impacts expression of virulence factors; 2) saeR/S appears to play a role in integrating cell density signaling with cues from the environmental stimuli; and 3) saeR/S was highly up-regulated during interaction with human PMNs in five virulent strains of S. aureus. Based on these observations (from our group and others), the focus of this proposal is to determine the function of saeR/S in S. aureus pathogenesis. This will be achieved by studies directed at two specific aims. The first aim will identify the role of saeR/S during interaction with PMNs using an isogenic saeR/S deletion mutant in S. aureus strain MW2 (pulse-field type USA400). This aim will be accomplished by creating a saeR/S deletion mutant and investigating PMN phagocytosis, ROS production, and bactericidal activity toward the saeR/S mutant and wild-type strains. In addition, this aim will determine if saeR/S is induced in wild-type S. aureus by specific PMN components. Oligonucleotide microarrays will also be used to gain a comprehensive analysis of the influence of saeR/S on the S. aureus virulon. The second aim will determine if saeR/S is important for S. aureus virulence using murine models of S. aureus infection. Mouse models will consist of soft-tissue and bacteremia and will be analyzed by histopathology of infected tissues. In summary, we anticipate these studies will provide valuable insight into the role of saeR/S in S. aureus pathogenesis. Perhaps more importantly, the proposed research should identify pathogenic strategies used by S. aureus to initiate infection.