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.

Public Health Relevance

Periodontal diseases are prevalent and associated with human systemic illness. The diseases are triggered by a group of highly proteolytic anaerobes, which is often referred to as 'red- complex'bacteria. The oral spirochete Treponema denticola, a member of the 'red-complex'bacteria, is strongly associated with severe and refractory periodontal diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE023080-02
Application #
8703071
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14260