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

SAER/S 基因调控系统在侵袭性葡萄球菌感染中的作用

• 批准号: 8168415
• 负责人: Jovanka M Voyich
• 金额: $ 20.73万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168415
• 关键词: Attenuated; Cessation of life; Communities; Computer Retrieval of Information on Scientific Projects Database; Disease; Funding; Gene Components; Gene Expression; Genes; Grant; Hospitals; Immune response; Incidence; Individual; Infection; Inflammatory; Institution; Integration Host Factors; Morbidity - disease rate; Mus; Necrotizing fasciitis; Pathology; Phagocytosis; Pneumonia; Regulator Genes; Research; Research Personnel; Resources; Role; Sepsis; Skin; Soft Tissue Infections; Source; Staphylococcal Infections; Staphylococcus aureus; System; United States; United States National Institutes of Health; Virulence; base; design; human mortality; methicillin resistant Staphylococcus aureus; mortality; mouse model; mutant; pathogen

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 耐甲氧西林金黄色葡萄球菌（MRSA）在医院和社区都是一个问题，现在是人类死亡的主要原因，仅在美国，2005年估计就有18，650例死亡与侵袭性MRSA感染有关。 近年来，社区耐甲氧西林链球菌的发病率呈上升趋势。金黄色葡萄球菌（CA-MRSA）感染的健康个体。这些新出现的菌株引起皮肤和软组织感染，但最突出的菌株也与严重的病理学有关，包括败血症，坏死性肺炎和坏死性筋膜炎。该提案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S.金黄色葡萄球菌促进炎症宿主反应，导致在侵袭性葡萄球菌感染中观察到的严重病理学。 这一假设是基于初步的发现，表明：1）显着减弱的生存saeR/S突变株（MW delta saeR/S）中性粒细胞吞噬后; 2）感染MW delta-saeR/S的小鼠侵袭性感染模型中没有死亡率和发病率;和3）saeR/S改变具有不同功能的多种基因中的基因表达的证据，包括参与逃避吞噬作用的那些，和毒性。 基于这些结果，设计了三个特定目的，以全面评估saeR/S在侵袭性葡萄球菌疾病中的作用。