Role of the Staphylococcus aureus SaeR/S Regulatory System in Neutrophil Evasion

金黄色葡萄球菌 SaeR/S 调节系统在中性粒细胞逃逸中的作用

• 批准号: 8690746
• 负责人: Jovanka M Voyich
• 金额: $ 35.63万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690746
• 关键词: Address; Antibiotics; Attenuated; Bacterial Infections; Binding; Biological Assay; Cessation of life; Communities; Complex; Consensus Sequence; Cytolysis; Cytoplasmic Granules; Data; Disease; Effectiveness; Environment; Exposure to; Gene Components; Gene Targeting; Genes; Goals; Hospitals; Human; Immune response; Incidence; Individual; Infection; Infectious Skin Diseases; Integration Host Factors; Kinetics; Knowledge; Lead; Life; Methicillin Resistance; Methods; Molecular; Morbidity - disease rate; Natural Immunity; Pathogenesis; Phagocytosis; Phenotype; Plasmids; Pneumonia; Positioning Attribute; Prevention strategy; Public Health; Publishing; Reactive Oxygen Species; Recombinants; Regulation; Regulator Genes; Research; Role; Septicemia; Severity of illness; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; System; Testing; Transcript; Transcriptional Regulation; United States; Virulence; Virulence Factors; base; clinically relevant; direct application; extracellular; human disease; human morbidity; human mortality; improved; in vivo; insight; killings; methicillin resistant Staphylococcus aureus; mortality; mouse model; mutant; neutrophil; novel; pathogen; promoter; resistant strain; response; skin abscess; treatment strategy

DESCRIPTION (provided by applicant): Staphylococcus aureus (S. aureus) is a leading cause of human infections worldwide, resulting in a diverse spectrum of disease severity from mild to life-threatening. Recently, there has been an increase in the incidence of community-associated methicillin-resistant S. aureus (CA-MRSA) infections in otherwise healthy individuals, the basis of which is largely unknown. Human polymorphonuclear leukocytes (PMNs or neutrophils) are the first line of defense against bacterial infections. The ability of S. aureus to circumvent destruction by innate immunity includes survival after PMN phagocytosis. The ability of S. aureus to survive following PMN phagocytosis is dependent on the pathogen's ability to sense and survive the hostile PMN environment. However, specific mechanisms used by S. aureus to evade PMN killing are incompletely defined. We hypothesize that the SaeR/S two-component regulatory system directly regulates S. aureus factors that impair an effective neutrophil response resulting in pathogen survival. This hypothesis is based on the following published and preliminary observations: 1) saeR and saeS transcripts were up-regulated following PMN phagocytosis; 2) deletion of saeR/S significantly decreased survival of S. aureus following human PMN phagocytosis; and 3) transcriptional assays identified extracellular virulence genes down- regulated in saeR/S and direct binding of recombinant SaeR to a consensus sequence within several of these virulence gene promoters. These data correlate well with in vivo studies that demonstrate SaeR/S regulates factors vital for S. aureus - induced morbidity following skin infections and mortality following invasive infections. To determine the molecular mechanisms behind the saeR/S-dependent phenotype we will first define the kinetics of activation of SaeR/S-regulated genes in response to PMN phagocytosis. Next, we will determine the contribution of individual SaeR/S-target genes to S. aureus survival and PMN lysis. Finally, we will assess expression of saeR/S-target genes in vivo and identify the contribution of individual genes regulated by saeR/S to S. aureus pathogenesis. Completion of this research will identify the specific effectors regulated by saeR/S responsible for survival following PMN phagocytosis and will define their contribution to PMN lysis and S. aureus pathogenesis in vivo. These findings will improve our understanding of the initial host-pathogen interactions that lead to S. aureus infection. This knowledge is predicted to have direct application for novel prevention and treatment strategies for staphylococcal infections.

性状（由申请人提供）：金黄色葡萄球菌（S.金黄色葡萄球菌）是全世界人类感染的主要原因，导致从轻度到危及生命的多种疾病严重程度。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，其基础在很大程度上是未知的。人类多形核白细胞（PMN或中性粒细胞）是抵抗细菌感染的第一道防线。S.金黄色葡萄球菌规避先天免疫破坏的方法包括在PMN吞噬作用后存活。S.金黄色葡萄球菌在PMN吞噬作用后存活取决于病原体感知并在不利的PMN环境中存活的能力。然而，S.金黄色葡萄球菌逃避PMN杀伤的机制尚不完全明确。我们假设SaeR/S双组分调节系统直接调节S。金黄色葡萄球菌因子损害有效的中性粒细胞反应，导致病原体存活。这一假说是基于以下已发表的和初步的观察结果：1）saeR和saeS转录本在PMN吞噬后上调; 2）saeR/S的缺失显著降低了S.在人PMN吞噬作用后的金黄色葡萄球菌;和3）转录测定鉴定了在saeR/S中下调的细胞外毒力基因，并鉴定了重组SaeR与这些毒力基因启动子中的几个内的共有序列的直接结合。这些数据与证明SaeR/S调节S.金黄色葡萄球菌引起的皮肤感染后的发病率和侵袭性感染后的死亡率。为了确定SaeR/S依赖性表型背后的分子机制，我们将首先确定SaeR/S调节基因响应PMN吞噬作用的激活动力学。接下来，我们将确定单个SaeR/S靶基因对S的贡献。金黄色葡萄球菌存活和PMN溶解。最后，我们将评估体内saeR/S靶基因的表达，并确定由saeR/S调控的单个基因对S的贡献。金黄色葡萄球菌发病机制这项研究的完成将确定由saeR/S调节的负责PMN吞噬后存活的特异性效应物，并将确定它们对PMN溶解和S。金黄色葡萄球菌体内致病性。这些发现将提高我们对导致沙门氏菌的最初宿主-病原体相互作用的理解。金黄色葡萄球菌感染。这些知识预计将直接应用于葡萄球菌感染的新预防和治疗策略。