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: 8560243
• 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
• 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/8560243
• 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

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）：螺旋体齿垢密螺旋体 (Td) 与严重和难治性牙周病密切相关。作为“红色复合体”细菌的一员，Td 主要生活在与牙龈直接接触的龈下菌斑的顶端表面。 上皮。因此Td处于最前沿，直接遭遇巨大的宿主免疫攻击，例如补体杀伤和吞噬作用。在口袋中，多吗啡酮透明白细胞（PMN）是主要的免疫细胞，通过吞噬作用杀死病原体来保护宿主。此外，龈缝液（GCF）主要由血清组成，含有补体系统，是宿主防御的关键组成部分。之前的报告表明，Td 对补体杀伤具有抵抗力，能够调节 PMN，并能在口腔菌群中茁壮成长。然而，所涉及的分子机制仍然难以捉摸。本申请的中心假设是 TDE0362 (Tmac) 是 Td 的一种新毒力因子，具有双重功能：其 C 末端 (C362) 是一种蛋白酶，可裂解对于 PMN 激活和补体杀伤至关重要的免疫因子；它的 N 末端 (N362) 包含一个细菌免疫球蛋白 (Big) 样结构域，可通过分子模拟机制阻止 PMN 激活。总的来说，Tmac 保护 Td 免受吞噬作用和补体杀伤，从而增强其存活和感染的建立。为了检验这一假设，本申请将重点关注以下具体目标：（1）确定Tmac是否被裂解和分泌，以及裂解所涉及的机制； (2) 研究Tmac对人IgG的内肽酶活性； (3)阐明Tmac在PMN激活中的作用及其机制； (4)研究Tmac在体外和体内Td致病性中的作用。该项目的完成将增进我们目前对 Td 致病性的理解，特别是先天免疫逃避机制，这可能会导致针对牙周病的新的治疗干预措施。