Exploring new virulence factors of the oral spirochete Treponema denticola

探索口腔螺旋体齿垢密螺旋体的新毒力因子

• 批准号: 10371498
• 负责人: Chunhao Chris Li
• 金额: $ 4.63万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371498
• 关键词: Address; Anaerobic Bacteria; Bacteria; Biochemical; Cardiovascular Diseases; Caspase; Complement; Complement Activation; Complex; Endodontics; Flagellin; Funding; Goals; Immune; Immune response; Impairment; Infection; Inflammation; Innate Immune Response; Innate Immune System; Lead; Mastigophora; Mediating; Modification; Molecular; Mouth Carcinoma; Neuraminidase; Neutrophil Activation; Oral cavity; Pathogenicity; Periodontitis; Play; Polysaccharides; Proteins; Refractory; Role; Sialic Acids; Structure; Symbiosis; Tissues; Treponema denticola; Virulence Factors; cell motility; dysbiosis; glycosylation; insight; killings; microbial; microbiota; neutrophil; novel; novel strategies; oral bacteria; oral microbial community; oral spirochetes; parent grant; pathogen; prevent; trait

Abstract (Parent Grant) The innate immune system (i.e., complement- and neutrophil-mediated killing) is the first line of defense against microbial infections. In the oral cavity, the innate immune system is highly active and sustains the oral microbiota at the stage of symbiosis. As a keystone pathogen, the oral bacterium Treponema denticola (Td) is highly invasive, establishing itself at the forefront of subgingival plaques where it directly confronts the host immune response. Td is able to breach host immune defenses, survives, and even becomes predominant in the pocket when dysbiosis and inflammation worsens (e.g., in severe and refractory periodontitis). The underlying mechanisms that allow Td to evade the host immune response remain largely unknown. During the last funding cycle, we have discovered several novel virulence factors in Td. Among these factors, we found that TDE0362 (a cysteine protease) and TDE0471 (a sialidase) have unique biochemical and structural features, protect Td from complement and neutrophils killings, and play pivotal roles in the pathogenicity of Td. We also identified a novel glycan that modifies Td flagellin proteins and this unique modification is not only essential for the flagellation and motility of Td but also alters the innate immune response to the flagellins. Building upon these findings, this renewal aims to elucidate the molecular mechanisms underlying these three novel pathogenic traits of Td. To achieve this goal, the following three questions will be addressed. (1) What is the molecular mechanism by which TDE0362 impairs host neutrophil and complement activation? (2) How does TDE0471 utilize host sialic acids to protect Td from complement killing? (3) How does glycosylation alter the innate immune response to Td flagellins? Completion of these studies will not only provide new insights into understanding the pathogenicity of Td at the molecular level, but also advance our current understanding of the uniqueness and complexity of periodontitis. One of the unique aspects about keystone pathogens is that while they trigger robust and hostile inflammation, they have also evolved complex mechanisms to evade host immune defenses, which allow them to thrive in the pocket, change symbiotic microbiota to dysbiosis, and cause tissue damage. Understanding their uniqueness and the underlying mechanisms will lead to new strategies to treat and prevent periodontitis.

摘要（家长补助金） 先天免疫系统（即，补体介导的杀伤作用）是第一道防线 对抗微生物感染在口腔中，先天免疫系统高度活跃， 口腔微生物群处于共生阶段。作为一个关键的病原体，口腔细菌密螺旋体 齿垢（Td）是高度侵入性的，在龈下菌斑的最前沿建立自己， 直接对抗宿主的免疫反应TD能够突破宿主的免疫防御，存活下来， 甚至在微生态失调和炎症发生时在袋中成为主要的（例如，严重 和难治性牙周炎）。使Td逃避宿主免疫的潜在机制 反应仍然很大程度上未知。在上一个融资周期，我们发现了几个新的 毒力因子在这些因素中，我们发现TDE 0362（半胱氨酸蛋白酶）和 TDE 0471（一种唾液酸酶）具有独特的生化和结构特征， 和嗜中性粒细胞杀伤，并发挥关键作用的致病性TD。我们还发现了一本小说 修饰Td鞭毛蛋白的聚糖，这种独特的修饰不仅是必需的， 鞭毛蛋白不仅影响Td的鞭毛形成和运动性，而且还改变对鞭毛蛋白的先天免疫应答。基础上 这些发现，本次更新的目的是阐明这三个新的分子机制 致病性状为实现这一目标，将解决以下三个问题。(1)什么 是TDE 0362损害宿主中性粒细胞和补体激活的分子机制？（二） TDE 0471如何利用宿主唾液酸保护Td免受补体杀伤？(3)如何 糖基化会改变对Td鞭毛蛋白的先天免疫反应吗？完成这些研究将不会 不仅为在分子水平上理解Td的致病性提供了新的见解，而且 促进我们目前对牙周炎的独特性和复杂性的理解。一个独特的 关于关键病原体的一个方面是，虽然它们会引发强烈和敌对的炎症，但它们具有 还进化出复杂的机制来逃避宿主的免疫防御，这使得它们能够在宿主体内茁壮成长。 口袋，将共生微生物群改变为生态失调，并导致组织损伤。了解他们的 牙周炎的独特性和潜在的机制将导致新的策略来治疗和预防牙周炎。