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

基本信息

批准号：
10796349
负责人：
Chunhao Chris Li
金额：
$ 5.71万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-17 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10796349
关键词：
Address Anaerobic Bacteria Animal Model Bacteria Biochemical C-terminal Cardiovascular Diseases Caspase Catalysis Cell Line Cell surface Complement Complement Activation Complement Factor H Complement Membrane Attack Complex Complex Cryo-electron tomography Crystallography Deposition Endodontics Environment Enzymes Escherichia coli Flagella Flagellin Funding Genetic Genomics Goals Grant Immune Immune Evasion Immune response Immune system Immunoglobulin G Impairment Infection Inflammation Innate Immune Response Innate Immune System Knowledge Mastigophora Mediating Modification Molecular Mouth Carcinoma Mutation N-terminal Neuraminidase Neutrophil Activation Oral cavity Pathogenicity Pattern Recognition Peptide Hydrolases Peptides Periodontal Pocket Periodontitis Phagocytosis Play Polysaccharides Porphyromonas gingivalis Proteins Proteomics Refractory Reporting Role Serum Sialic Acids Site Structure Symbiosis TLR2 gene TLR5 gene Techniques Testing Tissues Treponema denticola Virulence Factors Work X-Ray Crystallography Zinc bactericide cell motility complement system dysbiosis glycosylation insight killings microbial microbiota migration neutrophil novel novel strategies oral bacteria oral microbial community oral spirochetes pathogen periodontopathogen prevent receptor structural biology tool trait

项目摘要

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 motile and 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 periodontal 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 found that 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 specific 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? Addressing these questions 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 the 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 oral cavity, change symbiotic microbiota to dysbiosis, and cause tissue damage. In this regard, understanding their uniqueness and underlying mechanisms will lead to new strategies to treat and prevent periodontitis.

先天免疫系统（即补体和中性粒细胞介导的杀伤）是第一道防线防御微生物感染。在口腔中，先天免疫系统高度活跃，维持共生阶段的口腔微生物群。作为主要病原体，口腔细菌齿垢密螺旋体 (Td) 具有高度活动性和侵袭性，在消灭病毒方面处于领先地位。龈下菌斑，直接面对宿主的免疫反应。 Td 能够破坏主机免疫防御，存活下来，甚至在牙周袋中占据主导地位生态失调和炎症恶化（例如，严重和难治性牙周炎）。底层的 Td 逃避宿主免疫反应的机制仍然很大程度上未知。期间在上一个资助周期中，我们发现了 Td 中的几个新的毒力因子。在这些因素中，我们发现TDE0362（一种半胱氨酸蛋白酶）和TDE0471（一种唾液酸酶）具有独特的生化和结构特征，保护 Td 免受补体和中性粒细胞的杀伤，并在 Td 的致病性。我们还鉴定了一种可以修饰 Td 鞭毛蛋白的新型聚糖，并发现这种独特的修饰不仅对于 Td 的鞭毛和运动至关重要，而且还改变对鞭毛蛋白的先天免疫反应。基于这些发现，本次更新旨在阐明 Td 的这三种新致病性状背后的分子机制。到为实现这一目标，将解决以下三个具体问题。 (1)什么是分子 TDE0362 损害宿主中性粒细胞和补体激活的机制是什么？ (2) 如何 TDE0471利用宿主唾液酸来保护Td免受补体杀伤？ (3)糖基化是如何进行的改变对 Td 鞭毛蛋白的先天免疫反应？解决这些问题不仅可以提供在分子水平上了解 Td 致病性的新见解，同时也推进了我们的研究目前对牙周炎的独特性和复杂性的认识。独特的方面之一关于关键病原体的一点是，虽然它们会引发强烈且敌对的炎症，但它们还进化出复杂的机制来逃避宿主的免疫防御，这使它们能够在口腔，使共生微生物群失调，并导致组织损伤。对此，了解其独特性和潜在机制将导致治疗和治疗的新策略预防牙周炎。