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: 8360161
• 负责人: Jovanka M Voyich
• 金额: $ 20.94万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360161
• 关键词: Accounting; Blood; Communities; Disease; Emerging Communicable Diseases; Foundations; Funding; Future; Gene Components; Grant; Human; Incidence; Individual; Infection; Infectious Skin Diseases; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Influentials; Interferon Type II; Interferons; Interleukin-2; Interleukin-6; Mediating; Mus; National Center for Research Resources; Pathogenesis; Peritonitis; Principal Investigator; Production; Regulator Genes; Research; Research Infrastructure; Resources; Role; Sepsis Syndrome; Source; Staphylococcal Infections; Staphylococcus aureus; System; TNF gene; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Virulence; Work; cost; cytokine; insight; methicillin resistant Staphylococcus aureus; mortality; mouse model; mutant; subcutaneous

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during invasive staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-¿), interferon gamma (IFN-¿), interleukin (IL)-6, and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study demonstrated robust saeR/S-mediated IFN-¿ production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes the relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators. This study provides a foundation for future work to identify the individual contributions of specific saeR/S-regulated factors to the host inflammatory response during staphylococcal disease.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 社区相关的耐甲氧西林金黄色葡萄球菌占葡萄球菌疾病发病率增加的很大一部分，并可导致从轻度皮肤感染到迅速致命的败血症综合征等各种疾病。目前，我们对金黄色葡萄球菌在侵袭性葡萄球菌疾病中的细菌致病机制和宿主炎症机制的了解有限。在此，我们利用金黄色葡萄球菌致病的小鼠模型，研究了SAER/S双组分基因调控系统在介导细胞因子诱导中的重要作用。侵袭性金黄色葡萄球菌感染可诱导局部和全身性促炎细胞因子的产生，包括肿瘤坏死因子α、干扰素γ、白介素6和白介素2。相比之下，感染SAER/S等基因缺失突变的小鼠表现出显著的促炎细胞因子水平降低。此外，受SAER/S影响的分泌因子可在体外诱导人血中的促炎细胞因子。我们的研究表明，在侵袭性皮肤感染和皮下感染中，Saer/S介导的干扰素-β的产生都很强。结果还表明，在金黄色葡萄球菌腹膜炎期间，SAER/S在促进细菌存活和增加宿主死亡率方面发挥了关键作用。综上所述，这项研究为金黄色葡萄球菌在葡萄球菌疾病中使用的特定机制提供了洞察力，并表征了细菌全球毒力调节因子与促炎介质产生之间的关系。本研究为进一步研究葡萄球菌病过程中特定的SAER/S调节因子在宿主炎症反应中的作用奠定了基础。