NEUTROPHILS AND STAPHYLOCOCCUS AUREUS

中性粒细胞和金黄色葡萄球菌

• 批准号: 6534221
• 负责人: Hattie D. Gresham
• 金额: $ 18.74万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534221
• 关键词: Staphylococcus aureus; Staphylococcus infection; cell migration; cellular immunity; chemokine; clinical research; cytokine receptors; genetically modified animals; human subject; laboratory mouse; microorganism immunology; neutrophil; virulence

Description (Adapted from applicant's abstract): Staphylococcus aureus is a major human pathogen causing significant morbidity and mortality in both community- and hospital-acquired infections. Concern over the emergence of multidrug resistant strains, particularly strains which lack sensitivity to all currently available antibiotics, has renewed interest in understanding the virulence mechanisms of this pathogen at the molecular level and in elucidating host defense elements which either provide protection from or which limit infection. Neutrophils (PMN) have long been thought to provide significant host defense against S. aureus infection. However, our studies of S. aureus-induced peritonitis and sepsis in mice have suggested that PMN have both a protective and a deleterious role. In order to demonstrate that PMN contribute to the pathogenesis of S. aureus infection, we have used multiple approaches which either limit or promote PMN migration into the infectious site. Our data indicate that excessive numbers of PMN and elevated levels of a C-X-C chemokine, MIP-2, at the site of a S. aureus infection create an environment which leads to enhanced extracellular replication of the pathogen and its intracellular survival in PMN to the detriment of the host; that PMN isolated from this environment are sufficient to establish infection in naive animals; that some of the bacteria inside these infected PMN are in endosomes with partially or fully degraded membranes; and that two regulatory loci mutants (agr- and sar-) which lack the expression of several virulence factors are less able to survive and/or avoid clearance in the presence of excess PMN and MIP-2. We hypothesize that S. aureus manifests as a virulence determinant the ability to exploit the host's inflammatory response in order to enhance its survival. Moreover, we hypothesize that exogenous modulation of the inflammatory response is sufficient to alter the susceptibility of the host to infection. To test this hypothesis, we will pursue the following specific aims: #1) determine the number of PMN necessary for protection and for their deleterious role in two models of S. aureus infection; #2) define the contribution of C-X-C chemokines, the CXCR2 receptor, and specific virulence factors expressed by S. aureus to the creation of the environment which leads to both enhanced extracellular replication and intracellular survival of the pathogen; #3) elucidate known virulence factors whose genes are activated both in vivo and in vitro specifically in the presence of C-X-C chemokines and PMN; and #4) determine the mechanism of uptake and the intracellular locale of wild-type and isogenic mutants of S. aureus taken up both in vivo and in vitro by C-X-C chemokine-stimulated PMN.

描述（改编自申请人的摘要）：金黄色葡萄球菌是一种 主要人类病原体在这两种疾病中造成显着的发病率和死亡率 社区和医院获得性感染。对出现的担忧 多重耐药菌株，特别是对所有药物均缺乏敏感性的菌株 目前可用的抗生素，人们重新燃起了了解抗生素的兴趣 在分子水平上阐明该病原体的毒力机制 宿主防御元件提供保护或限制 感染。中性粒细胞（PMN）长期以来被认为是重要的宿主 防御金黄色葡萄球菌感染。然而，我们对金黄色葡萄球菌诱导的研究 小鼠腹膜炎和败血症表明中性粒细胞具有保护作用 和一个有害的角色。为了证明 PMN 对 针对金黄色葡萄球菌感染的发病机制，我们使用了多种方法 限制或促进 PMN 迁移到感染部位。我们的数据 表明 PMN 数量过多和 C-X-C 水平升高 趋化因子 MIP-2 在金黄色葡萄球菌感染部位创造环境 这导致病原体及其细胞外复制增强 PMN 中的细胞内存活对宿主不利； PMN 被隔离 这种环境足以在幼稚动物中造成感染； 这些受感染的 PMN 内的一些细菌位于内体中 部分或完全降解的膜；以及两个调控位点突变体 (agr-和sar-)缺乏几种毒力因子表达的较少 能够在存在过量 PMN 和 MIP-2 的情况下生存和/或避免清除。 我们假设金黄色葡萄球菌表现为毒力决定因素 利用宿主的炎症反应来提高其生存率。 此外，我们假设炎症反应的外源性调节 足以改变宿主对感染的易感性。测试 根据这个假设，我们将追求以下具体目标：#1）确定 保护和有害作用所需的 PMN 数量有两个 金黄色葡萄球菌感染模型； #2) 定义 C-X-C 趋化因子的贡献， CXCR2 受体和金黄色葡萄球菌表达的特异性毒力因子 创造导致细胞外增强的环境 病原体的复制和细胞内存活； #3) 阐明已知的 其基因在体内和体外均被激活的毒力因子 特别是在 C-X-C 趋化因子和 PMN 存在的情况下；和 #4) 确定 野生型和同基因型的摄取机制和细胞内区域 C-X-C 在体内和体外摄取金黄色葡萄球菌突变体 趋化因子刺激的 PMN。