Mechanisms of Oral Streptococcus Macrophage Activation

项目摘要/摘要 牙周病是一种复杂的炎症性疾病，不是由单一的微生物引起的，而是一种 口腔微生物的非生物群落，共同促进疾病。与疾病相关的炎症 是由口腔生物膜的成员发起的，但宿主对微生物的反应包括炎症 巨噬细胞的反应是疾病进展的主要原因。戈登链球菌是一种正常的 口腔无害的居住者，但也参与牙周病的进展，部分是通过 促进更多病原菌的定植。尽管戈登葡萄球菌和巨噬细胞都是单独的 在牙周病进展中很重要，但对它们之间的相互作用知之甚少。我们已经找到了一本小说，不过 反直觉的，巨噬细胞和戈登葡萄球菌之间的关系，在那里细菌更能存活 促进炎症表型类似的巨噬细胞释放细胞因子 那些在疾病期间出现的人。然而，人们对口语的机械性理解还存在着差距 链球菌-免疫与巨噬细胞的相互作用，以及这种相互作用的变化可能如何有助于 戈登葡萄球菌和/或巨噬细胞促进疾病的能力。这个项目的总体目标是 研究观察到的戈登氏链球菌免疫后果背后的机制 炎性巨噬细胞。中心假设是戈登葡萄球菌通过以下方式使炎症持久 主动破坏巨噬细胞吞噬小体，激活胞浆炎症小体，a 随后的促炎反应。为了研究这一假设，本项目旨在(1)定义 戈登氏链霉菌通过以下途径促进炎症反应的巨噬细胞机制 巨噬细胞和(2)检测体内炎性巨噬细胞对 戈登氏链霉(S.gordonii)为了实现这些目标，从经典的细胞生物学到生物化学，有各种各样的技术 将使用先进的显微镜、流式细胞仪和动物模型等技术。本项目竣工 将是理解共生体和先天免疫系统动态相互作用的有价值的一步 以及这两种基因如何在疾病进展中发挥作用。它还将为调查人员提供多样化的指导， 如提案中进一步概述的那样，进行科学和专业培训，以便成功过渡到下一阶段 独立领导一个成功的研究团队的阶段。

Project Summary/Abstract Periodontal disease is a complex inflammatory disease resulting not from a single organism, but rather a dysbiotic community of oral microbes working together to promote disease. Inflammation associated with disease is initiated by members of the oral biofilm, but the host response to the microorganisms, including inflammatory reactions by macrophages, is primarily responsible for disease progression. Streptococcus gordonii is a normally innocuous inhabitant of the oral cavity but is also involved in the progression of periodontal disease, partially by promoting colonization of more pathogenic bacteria. Although both S. gordonii and macrophages are individually important in periodontal disease progression, little is known about their interactions. We have found a novel, yet counterintuitive, relationship between macrophages and S. gordonii where the bacterium is better able to survive within, and promote enhanced cytokine release from macrophages with an inflammatory phenotype similar to those present during disease. However, there remains a gap in the mechanistic understanding of oral streptococcus-immune interactions with macrophages, and how changes in this interaction may contribute to the ability of S. gordonii and/or macrophages to contribute to disease. The overall objective of this project is to examine the mechanisms behind the observed immune consequences of S. gordonii interaction with inflammatory macrophages. The central hypothesis is that S. gordonii perpetuates inflammation by actively damaging macrophage phagosomes and activating the cytoplasmic inflammasome, a subsequent pro-inflammatory response. To investigate this hypothesis this project aims to (1) define the macrophage cellular mechanisms manipulated by S. gordonii to promote inflammatory response by macrophages and (2) examine the acute responses of in vivo inflammatory macrophages responding to S. gordonii. To achieve these aims a wide variety of techniques, from classical cell biology and biochemical techniques to advanced microscopy, flow cytometry and animal models will be used. Completion of this project will be a valuable step in understanding the dynamic interplay of commensals and the innate immune system and how the two play a role in disease progression. It will also provide the investigator with diverse mentoring, scientific and professional training, as further outlined in the proposal, to allow a successful transition to the next stage of independently leading a successful research team.