Studying the Protective Effects of Normal Oral Flora

研究正常口腔菌群的保护作用

• 批准号: 9982063
• 负责人: Xuesong He
• 金额: $ 47.75万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982063
• 关键词: Address; Animals; Bacteria; Biological Models; Cell physiology; Clinical; Communities; Data; Development; Escherichia coli; Event; Foundations; Future; Goals; Health; Host resistance; Human; Hydrogen Peroxide; Indigenous; Invaded; Laboratories; Lead; Mediating; Mediator of activation protein; Microbe; Molecular; Mus; Oral; Pathogenesis; Play; Production; Publishing; Regulation; Research; Resistance; Role; Science; Side; Signal Transduction; System; Testing; Virulence Factors; Work; base; clinically relevant; fighting; gut colonization; gut microbiota; human microbiota; in vitro Model; insight; interspecies communication; microbial; microbial community; microbiota; normal microbiota; novel therapeutic intervention; oral bacteria; oral microbial community; pathogen; prevent; protective effect; public health relevance; resistance mechanism; sensor; social structure

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.

抽象的： 当前大多数微生物发病机理研究都集中在了解不同的病毒因素如何可能 使病原体能够干扰并入侵正常的菌群。这项研究的重点是“故事的另一面”： 正常的菌群如何阻止和抵抗入侵外国病原体作为第一道防线。 了解宿主菌群对外国入侵的侵入性的基础机制 包括病原体在内的细菌具有极大的科学和临床重要性，这是其中的主要目标 应用。 在我们的初步研究中，我们建立了一个体外模型系统，用于研究社区级别 使用口服和肠道微生物，对不同来源细菌的侵袭性抗性 源自小鼠的社区。具体而言，我们确定了一个由三个组成的独特微生物联盟 鼠口腔微生物菌群中不同的细菌种类涉及限制肠道的侵袭 衍生的大肠杆菌。进一步的研究表明，这三个物种形成了独特的社会结构。他们 分别充当传感器，调解人和杀手，并在防止 将大肠杆菌整合到口腔微生物群落中。当我们的数据实现了复杂的信号事件时 该财团受到入侵物种的挑战。最有趣的是，我们证明了类似的 人类口腔微生物群落也存在耐药现象。基于这些 调查结果，我们假设基于土著微生物群对外国细菌的耐药性 是高度协调的社区级功能，涉及广泛的分子事件 认识外国入侵者，种间交流和受监管的杀戮产生 分子。了解这些分子事件将为受保护的人提供宝贵的见解 效果由普通菌群赋予。 我们认识到一个事实，即一项鼠类菌群研究将作为研究的理想模型系统 详细的分子机制以及为未来动物研究奠定基础 微生物群研究对于确定观察到的侵袭性的临床相关性至关重要 因此，机制该应用调查了这两个系统中的这种有趣现象。两个主 该应用的目标是：1）进一步了解使用侵袭性的分子机制 源自鼠口腔菌群的良好建立的三个物联盟模型系统； 2）解决 通过将研究扩展到人口腔微生物群，观察到的受保护机制的临床相关性。 这些研究的结果将提供有关正常菌群如何抵抗的有见地的机械信息 在分子水平上的外国病原体的入侵。这些关键信息可能直接导致新颖 试图增强普通菌群的受保护努力的治疗方法。