Studying the Protective Effects of Normal Oral Flora

摘要： 目前大多数微生物致病机制研究的重点是了解不同的毒力因子如何 使病原体干扰和侵入正常的植物群。本研究的重点是“故事的另一面”： 正常的植物群如何作为第一道防线来预防和抵抗外来病原体的入侵。 寄主植物群对外来入侵的抗性机制 细菌，包括病原体，具有重大的科学和临床重要性，这是本发明的主要目标。 应用程序. 在前期研究中，我们建立了一个研究社区水平的体外模型系统， 使用口腔和肠道微生物， 来自老鼠的群落具体来说，我们确定了一个独特的微生物财团组成的三个 小鼠口腔微生物植物群中参与限制肠道侵袭的不同细菌种类， 衍生的大肠杆菌。进一步的研究表明，这三个物种形成了一个独特的社会结构， 分别充当传感器、中介器和杀手，在预防 整合E.大肠杆菌进入口腔微生物群落。我们的数据暗示了复杂的信号事件， 该财团受到了入侵物种的挑战。最有趣的是，我们证明了一个类似的 在人类口腔微生物群落中也存在抗侵袭现象。基于这些 研究结果，我们假设本土微生物对外来细菌的入侵抵抗力 是一个高度协调的社区水平的功能，其中涉及广泛的分子事件， 识别外来入侵者，种间交流和控制生产的杀戮 分子。了解这些分子事件将提供有价值的见解， 正常植物群所产生的效果。 我们认识到这样一个事实，即小鼠微生物群研究将作为一个理想的模型系统，用于研究 详细的分子机制，并为未来的动物研究奠定基础， 微生物群研究对于确定所观察到的入侵抗性的临床相关性至关重要 因此，本申请研究了这两种系统中的有趣现象。两个主要 本申请的目的是：1）进一步了解利用 建立了小鼠口腔植物群的三种聚生体模型系统; 2）为了解决 通过将研究扩展到人类口腔微生物群，观察到的保护机制的临床相关性。 这些研究的结果将提供关于正常植物群如何抵抗 在分子水平上阻止外来病原体的入侵。这一关键信息可能直接导致新的 寻求增强正常植物群的保护作用的治疗方法。

Abstract: Most current microbial pathogenesis studies are focused on understanding how different virulence factors may enable pathogens to disturb and invade the normal flora. This study focuses on “the other side of the story”: how normal flora may prevent and resist the invasion of foreign pathogens as the first line of defense. Understanding the mechanisms underlying the invasion resistance of host flora against foreign invading bacteria, including pathogens, is of great scientific and clinical importance, which is the main goal of this application. During our preliminary studies, we established an in vitro model system for studying the community-level invasion resistance against the colonization of bacteria of different origin, using oral and gut microbial communities derived from mice. Specifically, we identified a unique microbial consortium composed of three distinct bacterial species within murine oral microbial flora that were involved in restricting invasion of gut- derived Escherichia coli. Further studies revealed that these three species form a unique social structure; they act as the sensor, the mediator and the killer, respectively, and have coordinated roles in preventing the integration of E. coli into oral microbial communities. Our data implicated sophisticated signaling events when the consortium was challenged with the invading species. Most intriguingly, we demonstrated that a similar invasion resistance phenomenon exists in the human oral microbial community as well. Based on these findings, we hypothesize that indigenous microbiota-based invasion resistance against foreign bacteria is a highly coordinated community-level function, which involves extensive molecular events for recognition of foreign invaders, inter-species communication and regulated production of killing molecules. Understanding these molecular events will provide valuable insights into the protective effect conferred by normal flora. We recognize the fact that a murine microbiota study will serve as an ideal model system for investigating the detailed molecular mechanisms as well as laying a foundation for future animal studies, and that a human microbiota study is critical for determining the clinical relevance of the observed invasion resistance mechanism, therefore, this application investigates this intriguing phenomenon in both systems. The two main goals of this application are: 1) To further understand the molecular mechanism of invasion resistance using the well established three-species consortium model system derived from murine oral flora; 2) To address the clinical relevance of the observed protective mechanism by expanding the study to human oral microbiota. The results of these studies will provide insightful mechanistic information on how the normal flora may resist the invasion of foreign pathogens at the molecular level. This critical information could lead directly to novel therapeutic approaches that seek to enhance the protective efforts of normal flora.