, a black-pigmented, Gram-negative anaerobe, is an important etiological agent of periodontal disease and is also linked to cardiovascular disease (22), rheumatoid arthritis (6,19) and other systemic diseases. The recent designation of P. gingivalis as a "keystone pathogen" (31) further highlights its ability to adapt to the harsh inflammatory conditions of the periodontal pocket and disrupt host-microbial homeostasis, which is partly responsible for the pathology observed in periodontal disease. Thus, to survive and orchestrate the microbial/host activities that can lead to disease, suggest that P. gingivalis possesses a complex regulatory network probably involving transcriptional and post-transcriptional mechanisms. While a key element in modulating the pathogenic potential of P. gingivalis is the post- translational modification of several of the major surface proteins/structures, there is a gap in our understanding of the components and mechanism(s) of this circuitry. The specific hypothesis to be addressed in this application is that via acetylation the novel vimA (virulence modulating) gene product is involved in the post-translational control of several major surface proteins in P. gingivalis including gingipain maturation/activation. In addition, VimA can also modulate the expression of several virulence genes by a transcriptional mechanism. This hypothesis is based on the observations made in the previous funding period where we have characterized the bcp-recA-vimA-vimE-vimF-aroG locus. This operon is essential for the maturation/activation/anchorage of the gingipains and regulation of other virulence factors of P. gingivalis. VimA is also important in oxidative stress resistance (4). Our data support a multifunctional role for VimA in modulating virulence in P. gingivalis possibly through its involvement in acetylation, that may affect A-LPS synthesis, protein sorting/transfer/anchorage and gene expression. In this project, we wish to extend these findings and to more fully clarify the VimA-dependent mechanism(s) of virulence regulation via acetylation. In bacteria including oral pathogens, the role of acetylation in virulence regulation has not been well characterized. The long term objective of our research program is to elucidate a comprehensive molecular mechanism(s) for virulence regulation in P. gingivalis as a prerequisite to the development of novel therapeutic interventions to aid in the control and prevention of diseases associated with this keystone pathogen. It is likely that VimA, which is involved in acetylation, may be a founding member of a novel transcriptional/post-translational control mechanism in Gram- negative anaerobic bacteria. The current application is designed for a comprehensive assessment of the multifunctional role of VimA.
The specific aims : (1) To evaluate the role of acetylation in protein maturation in P. gingivalis. (2) To explore the effectsof VimA-dependent acetylation on gene expression in P. gingivalis. Collectively, the results from this study will clarify the mechanistic role of VimA in virulence regulation in P. gingivalis. It should shed light on the acetylation regulatory network in P. gingivalis. It will generate a model system(s) that will yield important clues that will facilitate the development of novel therapeutic interventions to aid in the control and prevention of periodontal disease.

Public Health Relevance

The post-translational modification of several of the major surface proteins/structures is important for the pathogenic potential of P. gingivalis. The goal of this research is to characterize the novel VimA-dependent mechanism for virulence regulation in P. gingivalis via acetylation. 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 this regulatory system 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
High Priority, Short Term Project Award (R56)
Project #
2R56DE013664-10A1
Application #
8926083
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2000-04-01
Project End
2015-08-31
Budget Start
2014-09-24
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
$291,392
Indirect Cost
$106,967
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92354