NEUTROPHILS AND STAPHYLOCOCCUS AUREUS

中性粒细胞和金黄色葡萄球菌

• 批准号: 6747920
• 负责人: Hattie D. Gresham
• 金额: $ 22.05万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747920
• 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; 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 主要的人类病原体引起了两者的显着发病率和死亡率 社区和医院获得的感染。对出现的关注 多药抗性菌株，尤其是对所有人缺乏灵敏度的菌株 目前可用的抗生素，对了解 该病原体在分子水平和阐明中的毒力机制 主机防御要素可提供保护或限制的保护 感染。长期以来人们认为中性粒细胞（PMN）提供了重要的宿主 防御金黄色葡萄球菌感染。但是，我们对金黄色葡萄球菌诱导的研究 小鼠的腹膜炎和败血症已表明PMN具有保护性 和有害角色。为了证明PMN有助于 金黄色葡萄球菌感染的发病机理，我们使用了多种方法 限制或促进PMN迁移到传染性部位。我们的数据 表明过多的PMN和C-X-C水平升高 趋化因子，MIP-2，在金黄色葡萄球菌感染的位置创造环境 导致病原体及其其细胞外复制增强 PMN的细胞内存活率损害了宿主；那个PMN隔离了 从这个环境中足以在幼稚的动物中建立感染。 这些受感染的PMN中的某些细菌在内体中 部分或完全降解的膜；还有两个调节基因座突变体 （Agr-和sar-）缺乏几种毒力因子的表达较少 能够在过量的PMN和MIP-2存在下生存和/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以增强其生存。 此外，我们假设炎症反应的外源调节 足以改变宿主感染的敏感性。测试 这个假设，我们将追求以下特定目的：＃1）确定 保护及其在两个 金黄色葡萄球菌感染的模型； ＃2）定义C-X-C趋化因子的贡献， 金黄色葡萄球菌表达的CXCR2受体和特异性毒力因子 环境的创建，这两者都会增强细胞外 病原体的复制和细胞内存活； ＃3）阐明已知 其基因在体内和体外都被激活的毒力因子 特别是在C-X-C趋化因子和PMN的情况下； ＃4）确定 摄取机理和野生型和等源性的细胞内部位 金黄色葡萄球菌的突变体在体内和体外占据了C-x-C的体外 趋化因子刺激的PMN。