Mechanisms of Streptococcus gordonii survival within phagocytes

项目摘要 口腔细菌会加剧一些系统性疾病，尽管影响这些疾病的机制 具体过程尚不清楚。单核巨噬细胞在口腔侵袭清除中的一线管理 细菌常常在不知不觉中成为微生物传播的伙伴。然而，许多细节的 口腔微生物与吞噬细胞的细胞相互作用仍未得到很好的描述，包括如何 口腔微生物群失调导致的这些相互作用的变化可以使共生生物 变得致病。这项研究的总体目的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的洞察力 口腔微生物逃避免疫系统的机制，以减少这些 有机体对疾病的影响。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毒力决定因素是它们逃避由 吞噬细胞，然而允许这种颠覆的分子机制大多是未知的。这 提案将使用戈登链球菌作为口腔链球菌的模型，以确定其作用机制 对吞噬破坏产生抵抗力。中心假说是戈登氏链霉菌结合了 对活性氧物种(ROS)的抗性，具有主动破坏吞噬体的能力，以避免 这些免疫细胞的破坏。这一假说源于发表的报告显示口腔链球菌 可以在吞噬细胞内存活，初步数据表明具有毒力的戈登链球菌具有 增强的ROS抗性，防止吞噬小体成熟的能力，以及伴随而来的生存能力 在巨噬细胞内。这一假设将通过追求以下两个具体目标来检验：1)确定 戈登氏链霉菌毒力株提高吞噬细胞中ROS抗性和存活率的基因。 据推测，ROS抗性对戈登葡萄球菌在体内的杀灭具有重要的初始抵抗力 吞噬细胞，允许增加毒力潜力。为了达到这个目标，我们将确认我们的初步数据 关于戈登葡萄球菌特定基因的作用。2)了解吞噬小体破坏的机制 由S.Gordonii诱导。初步数据表明，活的戈登氏链球菌改变了 吞噬小体完全成熟到吞噬小体。据推测，细菌直接破坏了 吞噬体完整性。这个目标将测试细菌对吞噬小体的破坏，细菌诱导的 吞噬小体成熟改变和吞噬小体ROS产生。有了这些目标，我们将核实 解释ROS抗性的基本基因，并详细说明 致病性链球菌改变吞噬小体成熟动力学。综上所述，拟议研究将 提供关于口腔细菌通常共生的机制的基本见解 造成局部和系统性疾病，可用于治疗。

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.