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：
9894788
负责人：
Chunhao Chris Li
金额：
$ 39.48万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894788
关键词：
Address Anaerobic Bacteria Animal Model Bacteria Biochemical Biochemical Genetics C-terminal Cardiovascular Diseases Caspase Catalysis Cell Line Cell surface Cleaved cell Complement Complement Activation Complement Factor H Complement Membrane Attack Complex Complex Cryo-electron tomography 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 Lead Mastigophora Mediating Modification Molecular Mouth Carcinoma Mutation N Domain 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 Roentgen Rays Role Serum Sialic Acids Site Structure Symbiosis TLR2 gene TLR5 gene Techniques Testing Tissues Treponema denticola Virulence Factors Work X-Ray Crystallography Zinc bactericide base 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戮）是第一行防御微生物感染。在口腔中，先天免疫系统高度活跃，并且在共生阶段维持口腔菌群。作为基石病原体，口腔细菌 treponema denticola（TD）高度流动性和侵入性，确立了自己的最前沿尺寸斑块直接面对宿主免疫反应。 TD可以违反主机免疫防御，生存，甚至在牙周口袋中占主导地位营养不良和炎症恶化（例如，在严重和难治性牙周炎中）。基础允许TD逃避宿主免疫反应的机制在很大程度上未知。在最后的融资周期，我们在TD中发现了几个新型的毒力因子。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性特征，保护道路免受补体和中性粒细胞的杀戮，并在 TD的致病性。我们还确定了一种新的聚糖，可修饰TD鞭毛蛋白并发现这种独特的修改不仅对TD的鞭毛和运动至关重要，而且还会改变对鞭毛的先天免疫反应。在这些发现的基础上，这种更新的目的是阐明了这三个新型TD致病性状的分子机制。到实现此目标，将解决以下三个特定问题。（1）什么是分子 TDE0362损害宿主中性粒细胞和补体激活的机制？（2）如何 TDE0471利用宿主唾液酸保护TD免受补充杀戮？（3）糖基如何如何改变对TD鞭毛的先天免疫反应？解决这些问题不仅会提供关于了解分子水平上TD的致病性的新见解，但也推进了我们当前对牙周炎的独特性和复杂性的理解。独特的方面之一关于基石病原体，当它们引发强大而敌对的炎症时，它们有还发展了复杂机制以逃避宿主免疫防御措施，这使他们能够在口腔，将共生微生物群变成营养不良，并引起组织损伤。在这方面，了解它们的独特性和潜在机制将导致新的策略来治疗和预防牙周炎。