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）：密螺旋体（Td）与严重和难治性牙周疾病密切相关。作为“红色复合体”细菌的一员，Td主要生活在与牙齿直接接触的龈下菌斑的根尖表面