Mechanisms for adaptation to oxidative stress in Porphyromonas gingivalis Porphyromonas gingivalis, a black-pigmented, Gram-negative anaerobe, is an important etiologic agent of periodontal disease. The inflammatory environment of the periodontal pocket suggests that this organism has properties that will facilitate its ability live in an oxidative environment. There is a gap in our knowledge of mechanism(s) of oxidative stress resistance in P. gingivalis and other periodontal pathogens. It is our hypothesis that in P. gingivalis multiple coordinately regulated mechanisms are vital for protection against oxidative stress and are significant in the pathogenicity of the organism. In preliminary studies, we have used a global approach to assess the transcription profile of the cellular response of isogenic mutants of P. gingivalis in an environment of oxidative stress typical of the periodontal pocket. The response to hydrogen peroxide (H2O2)-induced oxidative stress identified the induced expression of several genes including some known to be involved in oxidative stress resistance. The duration of oxidative stress was shown to differentially modulate transcription with the up-regulation of DNA repair/modification genes mostly seen at a shorter exposure time. During a longer exposure to oxidative stress, several genes known to be involved in protein repair were up-regulated. Over the range of exposure times, there was an up-regulation of several hypothetical genes which have not been previously characterized. Our previous report has also demonstrated that, in contrast to other organisms, the repair of oxidative stress-induced DNA damage involving 8-oxo-7,8-dihydroguanine (8-oxoG) may occur by a yet-to-be described mechanism in P. gingivalis. In this project, we wish to gain a comprehensive understanding of how P. gingivalis adapts to the oxidative conditions typical of the periodontal pocket and evaluate whether it contributes to its pathogenicity.
The Specific Aims are: 1. To characterize the specific role(s) of oxidative stress-induced genes in the survival/pathogenicity of P. gingivalis. 2. To identify and characterize the regulatory sequences and protein(s) involved in the expression of the grpE locus. 3. To characterize the DNA damage and mechanism(s) of repair in isogenic mutants of P. gingivalis under conditions of oxidative stress. Collectively, this information could provide important clues that would allow the development of novel therapeutic interventions to aid in the control and prevention of periodontal disease and other P. gingivalis-associated diseases.

Public Health Relevance

The goal of this research is to characterize important factors that will facilitate the survival of the periodontal pathogen Porphyromonas gingivalis in the inflammatory environment of the periodontal pocket. Because this environment may cause severe damage to the organism and given its success as important cause of gum disease suggests that P. gingivalis has properties that will facilitate its ability live in a stress environment. Important factors that are essential for survival are prime targets for the development of novel therapeutics that will have a positive impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019730-04
Application #
8230809
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2009-06-08
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$354,134
Indirect Cost
$116,460
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Dou, Yuetan; Aruni, Wilson; Luo, Tianlong et al. (2014) Involvement of PG2212 zinc finger protein in the regulation of oxidative stress resistance in Porphyromonas gingivalis W83. J Bacteriol 196:4057-70
Aruni, A Wilson; Zhang, Kangling; Dou, Yuetan et al. (2014) Proteome analysis of coinfection of epithelial cells with Filifactor alocis and Porphyromonas gingivalis shows modulation of pathogen and host regulatory pathways. Infect Immun 82:3261-74
Aruni, A W; Robles, A; Fletcher, H M (2013) VimA mediates multiple functions that control virulence in Porphyromonas gingivalis. Mol Oral Microbiol 28:167-80
Henry, Leroy G; Aruni, Wilson; Sandberg, Lawrence et al. (2013) Protective role of the PG1036-PG1037-PG1038 operon in oxidative stress in Porphyromonas gingivalis W83. PLoS One 8:e69645
Seiberling, Kristin A; Aruni, Wilson; Kim, Shawn et al. (2013) The effect of intraoperative mupirocin irrigation on Staphylococcus aureus within the maxillary sinus. Int Forum Allergy Rhinol 3:94-8
Muthiah, Arun S; Aruni, Wilson; Robles, Antonette G et al. (2013) In Porphyromonas gingivalis VimF is involved in gingipain maturation through the transfer of galactose. PLoS One 8:e63367
Boutrin, Marie-Claire; Wang, Charles; Aruni, Wilson et al. (2012) Nitric oxide stress resistance in Porphyromonas gingivalis is mediated by a putative hydroxylamine reductase. J Bacteriol 194:1582-92
Henry, Leroy G; McKenzie, Rachelle M E; Robles, Antonette et al. (2012) Oxidative stress resistance in Porphyromonas gingivalis. Future Microbiol 7:497-512
Aruni, A Wilson; Lee, J; Osbourne, D et al. (2012) VimA-dependent modulation of acetyl coenzyme A levels and lipid A biosynthesis can alter virulence in Porphyromonas gingivalis. Infect Immun 80:550-64
Robles, A G; Reid, K; Roy, F et al. (2011) Porphyromonas gingivalis mutY is involved in the repair of oxidative stress-induced DNA mispairing. Mol Oral Microbiol 26:175-86

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