ROLE OF SAER/S DURING S AUREUS PATHOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 金黄色葡萄球菌(S.aureus)是世界范围内人类感染的主要原因，可引起从轻微到危及生命的各种疾病。金黄色葡萄球菌致病的能力在一定程度上是基于它颠覆先天免疫系统的能力。最近的研究表明，金黄色葡萄球菌可以逃避人类多形核白细胞(PMN或中性粒细胞)的杀伤。然而，人们对病原体如何检测先天免疫系统的组成部分做出反应并在宿主内生存的了解相对较少。因此，本研究的长期目标是更好地了解金黄色葡萄球菌的致病机理。具体的假设是金黄色葡萄球菌的两组分基因调控系统Saer/S有助于金黄色葡萄球菌逃避天然宿主防御，因此在致病机制中起重要作用。到目前为止，Voyich博士的实验室已经在金黄色葡萄球菌MW2株(脉冲场型USA400型)中产生了一个等基因的Saer/S缺失突变体。在中性粒细胞相互作用过程中，Saer/S突变体逃避人类中性粒细胞杀伤的能力大大减弱。寡核苷酸芯片显示，萨尔/S影响了金黄色葡萄球菌病毒子的大量基因。在菌血症小鼠模型中，SAER/S基因缺失显著降低了葡萄球菌的毒力。相反，他们发现MW2和突变的萨尔/S菌株在引起脓肿形成的能力上没有显著差异。综上所述，Saer/S在逃避中性粒细胞的杀伤中起着重要作用，是金黄色葡萄球菌菌血症过程中致病的关键因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 the S. aureus two  component gene regulatory systems saeR/S facilitates evasion of innate host defenses by S. aureus and is therefore important for pathogenesis. To date Dr. Voyich's lab has generated an isogenic saeR/S deletion mutant in S. aureus strain MW2 (pulse-field type USA400). During PMN interaction the saeR/S mutant was greatly attenuated in its ability to evade killing by human PMNs. Oligonucleotide microarrays indicate saeR/S influences a significant amount of genes of the S. aureus virulon. Deletion of saeR/S significantly attenuated staphylococcal virulence in a mouse model of bacteremia. In contrast, they saw no significant differences in ability between MW2 and the mutant saeR/S strain to cause abscess formation. In summary, saeR/S plays an important role in evasion of killing by PMNs and appears to be a critical factor conferring virulence during S. aureus bacteremia.