ROLE OF THE SAER/S GENE-REGULATORY SYSTEM IN INVASIVE STAPHYLOCOCCAL INFECTION

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。 耐甲氧西林金黄色葡萄球菌(MRSA)在医院和社区都存在问题，现在是人类死亡的主要原因，据估计，2005年仅在美国就有18650人死于侵袭性MRSA感染。近年来，社区相关耐甲氧西林金黄色葡萄球菌(CA-MRSA)感染在健康人群中的发病率呈上升趋势。这些新出现的菌株会导致皮肤和软组织感染，但最突出的菌株也与严重的病理有关，包括败血症、坏死性肺炎和坏死性筋膜炎。这项建议的长期目标是确定导致侵袭性葡萄球菌疾病的病原体和宿主因素。为此，我们研究了SAER/S双组分基因调控系统对侵袭性葡萄球菌疾病的影响。我们推测，受金黄色葡萄球菌Saer/S调控系统影响的细胞溶解因子促进了炎性宿主反应，导致了侵袭性葡萄球菌感染的严重病理。这一假说基于初步的研究结果，证明：1)SAER/S突变株(MWDelta-Saer/S)在多形核白细胞吞噬后的存活率显著降低；2)在MWDelta-Saer/S感染的小鼠的侵袭性感染模型中，没有出现死亡和发病现象；3)Saer/S突变株在包括参与逃避吞噬和毒力在内的多种功能基因中的基因表达发生了改变。基于这些结果，设计了三个具体目标，以提供对SAER/S在侵袭性葡萄球菌疾病中的作用的全面评估。

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. Methicillin-resistant Staphylococcus aureus (MRSA) is problematic both in hospitals and in the community and is now a major cause of human mortality, as an estimated 18, 650 deaths were associated with invasive MRSA infections during 2005 in the United States alone. In recent years, there has been an increase in the incidence of community-associated methicillin-resistant S. aureus (CA-MRSA) infections in healthy individuals. These emerging strains cause skin and soft-tissue infections, but the most prominent strains have also been associated with severe pathology, including sepsis, necrotizing pneumonia, and necrotizing fasciitis. The long-term objective of this proposal is to define the pathogen and host factors contributing to invasive staphylococcal disease. To that end, we have investigated the influence of the SaeR/S two-component gene-regulatory system on invasive staphylococcal disease. We hypothesize that cytolytic factors influenced by the SaeR/S regulatory system of S. aureus promote an inflammatory host response, resulting in the severe pathology seen in invasive staphylococcal infection. This hypothesis is based on preliminary findings demonstrating: 1) significantly attenuated survival of a saeR/S mutant strain (MWdelta saeR/S) after PMN phagocytosis; 2) absence of mortality and morbidity in a mouse model of invasive infection in mice infected with MWdelta-saeR/S; and 3) evidence of saeR/S altering gene expression in a wide variety of genes with diverse functions including those involved in evasion of phagocytosis, and virulence. Based on these results, three Specific Aims are designed to provide a comprehensive assessment of the role of saeR/S during invasive staphylococcal disease.