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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：
10596084
负责人：
Chunhao Chris Li
金额：
$ 45.52万
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/10596084
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