Porphyromonas gingivalis is an important etiologic agent of periodontal disease. The harsh inflammatory conditions of the periodontal pocket, in addition to the environmental changes encountered during infection and colonization, suggest that this organism has properties that will facilitate its ability to respond and adapt to stress. Stress response in the pathogen is a major determinant of its virulence. In general, the response and adaptation mechanisms are known to be mostly regulated at the level of transcription initiation by extracytoplasmic function (ECF) sigma factor, the largest group of alternative sigma factors. To date, little is known about the relationship between the regulation of adaptive mechanisms, virulence, and ECF sigma factors in P. gingivalis. Because the hostile environment within the host will likely affect the membrane architecture of the invading bacteria, it is our hypothesis that in P. gingivalis ECF ? factors coordinately regulate mechanisms vital for protection against environmental stress and are significant in the pathogenicity of the organism. In the genome of Porphyromonas gingivalis W83, six putative ECF ? factors were identified. In preliminary studies, we have inactivated five ECF ? factor genes (PG0162, PG0214, PG0985, PG1660, and PG1827) by allelic exchange mutagenesis. Taken together, our findings suggest that in P. gingivalis ECF sigma factors can modulate important virulence factors. ECF ? factors encoded by the PG0162 and PG1660 genes might also be involved in the post-transcriptional regulation of the gingipains. Bioinformatics analysis suggests that PG0162 and PG1660 are paralogs that have unique properties. It is likely that they may be involved in unique and complex regulatory mechanisms. In this project, we wish to gain a comprehensive understanding of P. gingivalis ECF ? factors and their role in an adaptive response to the environmental conditions typical of the periodontal pocket.
The Specific Aims are: (1) To confirm and characterize the properties of specific ECF sigma factors in P. gingivalis. (2) To identify the environmental stress signals and sensor protein(s) involved in the modulation of PG1660. (3) To identify the genes in the PG1660 regulon(s) and characterize the regulatory sequences involved in the expression of those genes. Collectively, the data generated will facilitate a comprehensive assessment of the role of ECF ? factors in regulating gene expression, identifying pathways of adaptation to environmental stress typical of the periodontal pocket and evaluating their impact on pathogenicity of P. gingivalis. Because many of the proteins in this study are unique, drugs designed to inhibit these targets could be an attractive therapeutic strategy to aid in the prevention of P. gingivalis-associated diseases.

Public Health Relevance

The goal of this research is to characterize the system(s) that will allow the pathogen Porphyromonas gingivalis to sense and adapt to the harsh environmental conditions of the periodontal pocket. Because of the success of this bacterium as an important cause of gum disease suggests that these systems are vital for its survival. Essential components of these systems 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 #
1R01DE022508-01A1
Application #
8398662
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (04))
Program Officer
Lunsford, Dwayne
Project Start
2012-07-18
Project End
2017-04-30
Budget Start
2012-07-18
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$355,500
Indirect Cost
$130,500
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
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Holden, Megan S; Black, Jason; Lewis, Ainsely et al. (2016) Antibacterial Activity of Partially Oxidized Ag/Au Nanoparticles against the Oral Pathogen Porphyromonas gingivalis W83. J Nanomater 2016:
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Dou, Y; Aruni, W; Muthiah, A et al. (2016) Studies of the extracytoplasmic function sigma factor PG0162 in Porphyromonas gingivalis. Mol Oral Microbiol 31:270-83
Boutrin, M-C; Yu, Y; Wang, C et al. (2016) A putative TetR regulator is involved in nitric oxide stress resistance in Porphyromonas gingivalis. Mol Oral Microbiol 31:340-53
McKenzie, R M E; Aruni, W; Johnson, N A et al. (2015) Metabolome variations in the Porphyromonas gingivalis vimA mutant during hydrogen peroxide-induced oxidative stress. Mol Oral Microbiol 30:111-27
Aruni, A Wilson; Dou, Yuetan; Mishra, Arunima et al. (2015) The Biofilm Community-Rebels with a Cause. Curr Oral Health Rep 2:48-56
Aruni, A Wilson; Mishra, Arunima; Dou, Yuetan et al. (2015) Filifactor alocis--a new emerging periodontal pathogen. Microbes Infect 17:517-30
Dou, Y; Robles, A; Roy, F et al. (2015) The roles of RgpB and Kgp in late onset gingipain activity in the vimA-defective mutant of Porphyromonas gingivalis W83. Mol Oral Microbiol 30:347-60

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