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（父母赠款） 先天免疫系统（即补体和中性粒细胞介导的杀戮）是第一道防线 针对微生物感染。在口腔中，先天免疫系统高度活跃并维持 在共生阶段的口腔微生物群。作为基石病原体，口服细菌treponema 牙本质（TD）具有高度侵入性，使自己处于subgingival斑块的最前沿 直接面对宿主免疫反应。 TD能够违反宿主免疫防御能力，生存，并且 当营养不良和炎症恶化时，即使在口袋中占主导地位（例如 和难治性牙周炎）。允许TD逃避宿主免疫的基本机制 响应在很大程度上未知。在最后一个资金周期中，我们发现了几本小说 TD中的毒力因子。在这些因素中，我们发现TDE0362（半胱氨酸蛋白酶）和 TDE0471（唾液酸酶）具有独特的生化和结构特征，可保护TD免受补体 和中性粒细胞杀死，并在TD的致病性中起关键作用。我们还确定了一本小说 可修饰TD鞭毛蛋白的聚糖，这种独特的修饰不仅对 TD的鞭毛和运动性，但也改变了对鞭毛蛋白的先天免疫反应。建立 这些发现，这种更新旨在阐明这三个新颖的分子机制 TD的致病性状。为了实现这一目标，将解决以下三个问题。 （1）什么 TDE0362损害宿主中性粒细胞和补体激活的分子机制是否存在？ （2） TDE0471如何利用宿主唾液酸保护TD免受补充杀害？ （3）如何 糖基化改变了对TD鞭毛蛋白的先天免疫反应？这些研究的完成不会 仅提供新的见解，以了解分子水平上TD的致病性，还提供 促进我们目前对牙周炎的独特性和复杂性的理解。独特之一 关于基石病原体的方面是，虽然触发强大而敌对的炎症，但它们具有 还发展了复杂机制以逃避宿主免疫防御措施，这使他们能够在 口袋，将共生微生物群变成营养不良，并导致组织损伤。了解他们 独特性和潜在机制将导致治疗和预防牙周炎的新策略。