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：
8703071
负责人：
Chunhao Chris Li
金额：
$ 39.14万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703071
关键词：
Anaerobic Bacteria Apical Bacteria Binding Binding Sites Bone Resorption C-terminal C3bi Calpain Cell surface Cells Cleaved cell Complement Complex Development Disease Endopeptidases Epithelium FCGR3B gene Fc Receptor Genomics Gingiva Goals Homologous Gene Host Defense Human ITGAM gene ITGB2 gene Immune Immunoglobulin Domain Immunoglobulin G In Vitro Infection Integrins Lead Lesion Leukocytes Liquid substance Macrophage-1 Antigen Mediating Metalloproteases Molecular Molecular Mimicry N-terminal Order Spirochaetales Pathogenesis Pathogenicity Peptide Hydrolases Periodontal Diseases Phagocytosis Play Protease Domain Proteomics Refractory Reporting Resistance Role Serum Streptococcus pyogenes Surface Testing Therapeutic Tissues Treponema denticola Virulence Factors Zinc base complement system in vivo infancy killings member neutrophil novel therapeutic intervention oral bacteria oral spirochetes pathogen public health relevance receptor

项目摘要

DESCRIPTION (provided by applicant): The spirochete Treponema denticola (Td) is strongly associated with severe and refractory periodontal conditions. As a member of the 'red-complex' bacteria, Td primarily lives on the apical surface of subgingival plaque in direct contact with the epithelium. Thus Td is at the forefront that directly encounters enormous host immune attacks, e.g., complement killing and phagocytosis. In the pocket, polymorphoneclear leukocytes (PMNs) are the major immune cells that protect the host by killing pathogens via phagocytosis. In addition, the gingival crevice fluid (GCF), which is mainly composed of serum, contains the complement system, a critical component in host defense. Previous reports suggest that Td is resistant to the complement killing, and is able to modulate PMNs and can thrive in the oral flora. However, the molecular mechanisms involved remain elusive. The central hypothesis of this application is that TDE0362 (Tmac), a new virulence factor of Td, has dual functions: its C-terminus (C362) is a protease that cleaves immune factors that are essential for the activation of PMNs and the complement killing; its N-terminus (N362) contains a bacterial immunoglobulin (Big)-like domain which blocks PMN activation via a molecular mimicry mechanism. Collectively, Tmac protects Td from the phagocytosis and the complement killing, and consequently enhances its survival and establishment of infection. To test this hypothesis, this application wil focus on the following Specific Aims: (1) To determine if Tmac is cleaved and secreted, and the mechanism involved in the cleavage; (2) To study the endopeptidase activity of Tmac on human IgG; (3) To elucidate the role of Tmac in PMN activation and its mechanism involved; and (4) To investigate the role of Tmac in the pathogenicity of Td in vitro and in vivo. Completion of this project will advance our current understanding of the pathogenicity of Td, in particular, the mechanisms involved in the innate immune evasion, which could potentially lead to new therapeutic interventions against periodontal diseases.

描述（由申请人提供）：螺旋体treponema denticola（TD）与严重和难治性的牙周条件密切相关。作为“红色复合物”细菌的成员，TD主要生活在尺寸的顶部表面，直接接触上皮。因此，TD处于最前沿，直接遇到巨大的宿主免疫攻击，例如补体杀伤和吞噬作用。在口袋中，多形核白细胞（PMN）是通过吞噬作用杀死病原体来保护宿主的主要免疫细胞。此外，主要由血清组成的牙龈缝隙流体（GCF）包含补体系统，这是宿主防御中的关键组成部分。先前的报告表明，TD对补体杀戮具有抗性，并且能够调节PMN并可以在口腔菌群中壮成长。但是，涉及的分子机制仍然难以捉摸。该应用的核心假设是TDE0362（TMAC）是TD的新毒力因子，具有双重功能：其C-末端（C362）是一种蛋白酶，可以切断免疫因子，这对于PMN的激活和补体杀戮是必不可少的；它的N末端（N362）包含一个细菌免疫球蛋白（大）样结构域，该结构域通过分子模拟机制阻止PMN激活。总体而言，TMAC可保护TD免受吞噬作用和补体杀戮的侵害，从而增强其生存和建立感染。为了检验这一假设，该应用将重点放在以下特定目的上：（1）确定TMAC是否被裂解和分泌，以及涉及裂解的机制；（2）研究TMAC对人IgG的内肽酶活性；（3）阐明TMAC在PMN激活及其涉及的机制中的作用；（4）研究TMAC在体外和体内TD致病性中的作用。该项目的完成将提高我们对TD致病性的最新理解，特别是先天免疫逃避的机制，这可能会导致针对牙周疾病的新治疗干预措施。