The goal of this research is to characterize the role of Treponema denticola (Td) surface proteins in interaction of this human oral spirochete with host tissue, thereby gaining insight into mechanisms by which these organisms contribute to initiation and progression of periodontal disease. We focus on analysis of Td protein complexes that directly affect cells isolated from tissue comprising the periodontal ligament (PDL) that comprises the junction between the tooth and the alveolar bone of the tooth socket: specifically the PrtP lipoprotein protease complex (dentilisin) and the oligomeric Msp protein. Our overall hypothesis is that dentilisin and Msp are major contributors to Td cytopathic behavior in periodontal disease. To characterize their specific roles in microbe-host interactions, our approach is to utilize purified native and recombinant proteins as well as isogenic Td strains carrying defined mutations in individual components of these outer membrane complexes. We will first extend our ongoing studies characterizing dentilisin assembly in the Td outer membrane. Then, to further studies of host cell responses to Td challenge, we will (A) determine the mechanism of dentilisin-induced activation of pro-MMP-2 and (B) characterize MMP-2-dependent fibronectin fragmentation resulting from Td challenge of PDL cells. This project will test the hypothesis that dentilisin is an effector protein whose activity results in magnified downstream signaling effects that are likely to be significant in vivo. Our research team is uniquely positioned to conduct these studies, with combined expertise in spirochete molecular biology, extracellular matrix biology and cytopathology of inflammatory diseases. Completion of this project will contribute to both basic knowledge of spirochete molecular biology and to understanding of microbe-host interactions in chronic infections such as periodontal diseases.

Public Health Relevance

The overarching goal of this research is to determine the mechanisms by which Treponema denticola interacts with host tissue in the oral environment and contributes to the dysregulation of host tissue homeostasis pathways that leads to periodontitis. The proposed studies will directly support this goal by characterizing specific mechanisms by which T. denticola interacts with host cell proteins that control turnover of fibronectin, a key component of the extracellular matrix. Our research team, with demonstrated experience in genetic manipulation and functional assays of T. denticola behavior, as well as in fine-scale analysis of fibronectin binding activity, is uniquely qualified to conduct these studies

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE025225-05
Application #
9688531
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Chander, Preethi
Project Start
2015-07-01
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ateia, Islam M; Sutthiboonyapan, Pimchanok; Kamarajan, Pachiyappan et al. (2018) Treponema denticola increases MMP-2 expression and activation in the periodontium via reversible DNA and histone modifications. Cell Microbiol 20:
Shin, J M; Gwak, J W; Kamarajan, P et al. (2016) Biomedical applications of nisin. J Appl Microbiol 120:1449-65