Mechanisms of Streptococcus gordonii survival within phagocytes

戈登链球菌在吞噬细胞内的存活机制

• 批准号: 9181188
• 负责人: Jason G Kay
• 金额: $ 11.96万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181188
• 关键词: Accounting; Affect; Bacteria; Binding; Biological Assay; Blood; Cell surface; Cells; Cellular biology; Cytoplasm; Data; Disease; Eating; Endocarditis; Essential Genes; Excision; Future; Galactose Binding Lectin; Genes; Goals; Imagery; Immune; Immune system; Infective endocarditis; Inflammation; Invaded; Kinetics; Lead; Leukocytes; Life; Longitudinal Studies; Luminol; Mechanics; Microbe; Modeling; Molecular; Molecular Genetics; Mononuclear; Nature; Oral; Oral cavity; Organism; Periodontitis; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Play; Prevention strategy; Price; Process; Production; Proteins; Published Comment; Publishing; Reactive Oxygen Species; Recruitment Activity; Reporting; Research; Resistance; Risk Factors; Role; Streptococcus; Streptococcus gordonii; Systemic disease; Testing; Virulence; Virulent; base; commensal microbes; experience; fluorescein isothiocyanate dextran; insight; killings; luminescence; macrophage; microbial; microbial host; microorganism; mutant; oral bacteria; oral microbiome; oral streptococci; pathogen; prevent; soft drink; stem; uptake

Project Summary Oral bacteria exacerbate a number of systemic diseases, although the mechanisms influencing such processes are unclear. Mononuclear phagocytic cells, front-line managers in the removal of invading oral bacteria are often unwitting associates in the dissemination of microbes. However, many details of the cellular interactions of oral microorganisms with phagocytes remain poorly characterized, including how changes in these interactions resulting from oral microbiome dysbiosis can allow commensal organisms to become pathogenic. The overall aim of this research is to increase our understanding of the dynamic phagocyte interactions with oral bacteria. The long-term goal is to use insights regarding the molecular mechanisms by which oral microorganisms evade the immune system to reduce the contributions of these organisms to disease. Oral streptococci are associated with several systemic diseases, including infective endocarditis. An important virulence determinant of these bacteria is their ability to evade destruction by phagocytic cells, yet the molecular mechanisms allowing for this subversion are mostly unknown. This proposal will use Streptococcus gordonii as a model oral streptococcus to define the mechanisms by which resistance to destruction by phagocytosis occurs. The central hypothesis is that S. gordonii combines resistance to reactive oxygen species (ROS) with an active ability to damage phagosomes to avoid destruction by these immune cells. The hypothesis stems from published reports showing oral streptococci can survive within phagocytes and preliminary data indicating S. gordonii with virulence potential have increased ROS resistance, an ability to prevent phagosome maturation, and a concomitant ability to survive within macrophages. The hypothesis will be tested by pursuing the following two specific aims: 1) Identify genes responsible for increased ROS resistance and survival in phagocytes by virulent S. gordonii strains. It's hypothesized that ROS resistance imparts an important initial resistance to killing of S. gordonii within phagocytes, allowing for increased virulence potential. In this Aim we will confirm our preliminary data regarding the roles of the specific S. gordonii genes. 2) Understand the mechanics of phagosomal disruption induced by S. gordonii. Preliminary data indicates that live virulent S. gordonii alters the ability of phagosomes to fully mature to phagolysosomes. It's hypothesized that the bacterium directly disrupts phagosome integrity. This aim will test for bacterial-induced damage to phagosomes, bacterial-induced alteration of phagosomal maturation, and phagosomal ROS production. With these aims we will verify essential genes accounting for ROS resistance and detail the basic mechanisms underlying the ability of pathogenic streptococci to alter phagosome maturation kinetics. Taken together, the proposed studies will provide essential insights regarding the mechanisms through which normally commensal oral bacteria can contribute to both local and systemic disease, which may be exploited for treatment.

项目摘要 口腔细菌加剧了许多全身性疾病，尽管影响这些疾病的机制是复杂的。 过程不清楚。单核细胞吞噬细胞，一线管理人员在清除侵入口腔 细菌常常是微生物传播的不知情伙伴。然而，许多细节 口腔微生物与吞噬细胞的细胞相互作用仍然缺乏特征，包括如何 由口腔微生物组生态失调引起的这些相互作用的变化可使口腔微生物 变成致病的。这项研究的总体目标是增加我们对动态的理解， 吞噬细胞与口腔细菌的相互作用。长期目标是利用对分子生物学的认识， 口腔微生物逃避免疫系统以减少这些微生物的贡献的机制 有机体对疾病口腔链球菌与几种全身性疾病有关，包括感染性 心内膜炎这些细菌的一个重要的毒力决定因素是它们逃避破坏的能力， 吞噬细胞，但允许这种颠覆的分子机制大多是未知的。这 一项提案将使用戈登链球菌作为口腔链球菌的模型，以确定其机制， 发生对吞噬作用破坏的抵抗。中心假设是S.戈登尼联合公司 抗活性氧（ROS），具有主动破坏吞噬体的能力， 这些免疫细胞的破坏。这一假设源于已发表的报告，显示口腔链球菌 可以在吞噬细胞内存活，初步数据表明S.具有潜在毒力的戈登氏菌 增加的ROS抗性、阻止吞噬体成熟的能力以及伴随的存活能力 在巨噬细胞内。该假设将通过追求以下两个具体目标进行测试：1）识别 基因负责增加活性氧抗性和生存的吞噬细胞由有毒的S。戈登氏菌株。 据推测，ROS抗性赋予了一个重要的初始抗性杀死S。戈登内 吞噬细胞，允许增加的毒力潜力。在本目标中，我们将确认我们的初步数据 关于特定S的作用。戈登氏菌基因2)了解吞噬体破坏的机制 由S. gordonii。初步数据表明，活毒力S。gordonii改变了 吞噬体完全成熟为吞噬溶酶体。假设细菌直接破坏了 吞噬体完整性该目的将测试细菌诱导的对吞噬体的损伤，细菌诱导的对吞噬体的损伤，以及细菌诱导的对吞噬体的损伤。 吞噬体成熟和吞噬体ROS产生的改变。有了这些目标，我们将验证 解释ROS抗性的必需基因，并详细说明了ROS抗性的基本机制。 致病性链球菌改变吞噬体成熟动力学。综合起来，拟议的研究将 提供了关于正常口腔细菌可以 这可能导致局部和全身疾病，可用于治疗。