Periodontal disease, one of the most common infections of humans, has a polymicrobial etiology whereby groups of microorganisms exhibit synergistic pathogenicity. As a model system for the study of polymicrobial synergy we are investigating P. gingivalis-S. gordonii interactions. S. gordonii, an early colonizer of the plaque biofilm, provides an attachment substratum for the more pathogenic later colonizer P. gingivalis. Contact dependent signaling and metabolite perception initiate further accumulation of P. gingivalis and the development of a dual species community. Interspecies coadhesion is mediated by the short fimbriae (comprised of the Mfa1 structural subunit) of P. gingivalis that engage the Ssp surface proteins of S. gordonii. Within SspB several amino acid motifs within a region spanning residues 1167-1193 (designated BAR), dictate binding activity and specificity. Development, and later constraint, of community development depends on the balance of tyrosine phosphorylation (through the kinase Ptk1) and dephosphorylation (through the phosphatase Ltp1) within P. gingivalis, which controls expression of community effectors such as Mfa1 and LuxS. This tyrosine (de)phosphorylation dependent signal transduction pathway also converges on the expression genes encoding proteases, and a dual species community of P. gingivalis and S. gordonii is more pathogenic compared to either species alone in a murine alveolar bone loss model. The objectives of this study are to: i) characterize the structural and functional motifs of Mfa1 that interact with the BAR domain of SspB;ii) define the role of the P. gingivalis tyrosine kinase Ptk1 in regulatory networks that control heterotypic community development with S. gordonii;and iii) determine the responses of P. gingivalis to the streptococcal metabolite 4-aminobenzoate (pABA) that regulate community development and pathogenic potential. Successful completion of these objectives will provide novel structure and function information on the P. gingivalis Mfa1 fimbrial adhesin. In addition, we will unravel the interplay between tyrosine kinase (Ptk1) and phosphatase (Ltp1) activities in the signal transduction events that regulate community development. We will also generate novel information regarding metabolite sensing and its role in both community development and pathogenic potential. Our broad long-term goal is to translate this fundamental mechanistic information into the identification of novel targets for therapeutic intervention directed toward pathogenic community inhibition. As single target intervention can have limited utility, and has yet to yield any significant advances in periodontal therapeutic options, interference with multiple components of pathogenic community development, including adhesive and maturation events, may have a greater likelihood of success.

Public Health Relevance

Information that will be obtained from this study has the potential to be translated into the development of toothpastes or mouthrinses that can prevent disease causing organisms from accumulating on the teeth. These would reduce the ability of disease causing bacteria to persist in the mouth and consequently prevent or reduce the severity of gum disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE012505-16
Application #
8502872
Study Section
Special Emphasis Panel (ZRG1-MOSS-B (02))
Program Officer
Lunsford, Dwayne
Project Start
1998-09-01
Project End
2018-04-30
Budget Start
2013-05-02
Budget End
2014-04-30
Support Year
16
Fiscal Year
2013
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Louisville
Department
Dentistry
Type
Schools of Dentistry
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Lamont, Richard J; Hajishengallis, George (2015) Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med 21:172-83
Wright, C J; Wu, H; Melander, R J et al. (2014) Disruption of heterotypic community development by Porphyromonas gingivalis with small molecule inhibitors. Mol Oral Microbiol 29:185-93
Hendrickson, Erik L; Wang, Tiansong; Beck, David A C et al. (2014) Proteomics of Fusobacterium nucleatum within a model developing oral microbial community. Microbiologyopen 3:729-51
Wright, Christopher J; Xue, Peng; Hirano, Takanori et al. (2014) Characterization of a bacterial tyrosine kinase in Porphyromonas gingivalis involved in polymicrobial synergy. Microbiologyopen 3:383-94
Hajishengallis, George; Lamont, Richard J (2014) Breaking bad: manipulation of the host response by Porphyromonas gingivalis. Eur J Immunol 44:328-38
Wang, Qian; Wright, Christopher J; Dingming, Huang et al. (2013) Oral community interactions of Filifactor alocis in vitro. PLoS One 8:e76271
Wright, C J; Burns, L H; Jack, A A et al. (2013) Microbial interactions in building of communities. Mol Oral Microbiol 28:83-101
Hasegawa, Y; Nagano, K; Ikai, R et al. (2013) Localization and function of the accessory protein Mfa3 in Porphyromonas gingivalis Mfa1 fimbriae. Mol Oral Microbiol 28:467-80
Hirano, T; Beck, D A C; Wright, C J et al. (2013) Regulon controlled by the GppX hybrid two component system in Porphyromonas gingivalis. Mol Oral Microbiol 28:70-81
Whitmore, Sarah E; Lamont, Richard J (2012) Tyrosine phosphorylation and bacterial virulence. Int J Oral Sci 4:1-6

Showing the most recent 10 out of 47 publications