Mechanisms of Oral Streptococcus Macrophage Activation

项目总结/摘要 牙周病是一种复杂的炎症性疾病，不是由单一的生物体引起的，而是由一种 口腔微生物的生态失调共同促进疾病。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，包括炎症反应， 巨噬细胞的反应，主要负责疾病的进展。戈登链球菌是一种正常的 牙周病是口腔中的一种无害的生物，但也参与牙周病的进展，部分原因是 促进更多致病细菌的定植。虽然两个S。戈登氏菌和巨噬细胞 在牙周病的发展过程中，它们的相互作用知之甚少。我们找到了一本小说， 反直觉，巨噬细胞和S. gordonii在那里细菌能够更好地生存 内，并促进增强的细胞因子从巨噬细胞中释放， 那些在疾病期间存在的人。然而，在对口腔的机械理解方面仍然存在差距。 链球菌与巨噬细胞的免疫相互作用，以及这种相互作用的变化如何有助于 S的能力。戈登氏菌和/或巨噬细胞导致疾病。该项目的总体目标是 研究所观察到的S.戈登互动 炎症巨噬细胞中心假设是S.戈登氏菌使炎症持续存在， 主动破坏巨噬细胞吞噬体并激活细胞质炎性体， 随后的促炎反应。为了研究这一假设，该项目旨在（1）定义 巨噬细胞机制操纵的S. gordonii促进炎症反应， （2）检查体内炎性巨噬细胞对巨噬细胞的急性反应， S. gordonii。为了实现这些目标，从经典的细胞生物学和生物化学， 将使用先进的显微镜技术、流式细胞术和动物模型。完成本项目 将是理解机体和先天免疫系统动态相互作用的重要一步 以及两者在疾病进展中的作用。它还将为调查员提供各种指导， 科学和专业培训，如提案中进一步概述的那样，以便成功过渡到下一个 独立领导一个成功的研究团队。

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.