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： 目前大多数微生物发病机制研究的重点是了解不同的毒力因子如何影响 使病原体扰乱和侵入正常菌群这项研究的重点是“故事的另一面”： 正常菌群如何作为预防和抵抗外来病原体入侵的第一道防线。 了解宿主菌群对外来入侵抵抗力的机制 包括病原体在内的细菌具有重要的科学和临床重要性，这是本研究的主要目标 应用。 在我们的初步研究中，我们建立了一个体外模型系统来研究社区水平 利用口腔和肠道微生物对不同来源的细菌定植进行入侵抵抗 具体来说，我们发现了一个由三种微生物组成的独特微生物群落。 小鼠口腔微生物菌群中的不同细菌种类参与限制肠道入侵 进一步的研究表明，这三个物种形成了独特的社会结构； 分别充当传感器、中介者和杀手的角色，在防止 我们的数据表明，大肠杆菌整合到口腔微生物群落中时涉及复杂的信号事件。 最有趣的是，我们证明了类似的情况。 基于这些，人类口腔微生物群落也存在入侵抵抗现象。 研究结果表明，我们追求基于本土微生物群的对外来细菌入侵抵抗力 是一个高度协调的社区水平功能，涉及广泛的分子事件 对外来入侵者的识别、物种间的交流以及杀戮的规范生产 了解这些分子事件将为保护性提供有价值的见解。 正常菌群赋予的作用。 我们认识到，小鼠微生物群研究将作为研究微生物群落的理想模型系统。 详细的分子机制并为未来的动物研究奠定基础，并且人类 微生物群研究对于确定观察到的入侵抵抗的临床相关性至关重要 因此，该应用程序研究了两个系统中的这种有趣的现象。 该应用的目标是：1）进一步了解利用 源自小鼠口腔菌群的完善的三物种联合体模型系统 2) 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有关正常菌群如何抵抗的深刻机制信息 在分子水平上外来病原体的入侵这一关键信息可能会直接导致新的发现。 寻求增强正常菌群保护作用的治疗方法。