Date on Master's Thesis/Doctoral Dissertation

5-2015

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Scott, David

Committee Co-Chair (if applicable)

Suttles, Jill

Committee Member

Lamont, Richard

Committee Member

Miller, Richard

Committee Member

Warawa, Jonathan

Subject

Porphyromonas gingivalis; Periodontium--Infections

Abstract

More than 64 million people in the US suffer from some form of periodontal disease. Periodontal diseases are bacterial infections of the hard and soft tissues surrounding the teeth which can lead to tooth loss. Periodontal tissue destruction is caused by inflammatory host-pathogen interactions. Porphyromonas gingivalis is a major causative agent of periodontal diseases and is a keystone periodontal pathogen. The 55kDa immunodominant RagB outer membrane protein of P. gingivalis has been proposed to facilitate iron transport. However, potential interactions between RagB and the innate response have not been examined. RagB homologues in gut Bacteroidetes have been associated with inflammatory bowel disease. Therefore, we hypothesized that RagB aids in virulence of P. gingivalis and elicits a pro-inflammatory host response in innate cells. We determined that RagB exposure led to the differential and dose-related expression of multiple genes encoding pro-inflammatory mediators (IL-1β, IL-6, IL-8, and CCL2) in primary human monocytes and to the secretion of TNF, IL-6 and IL-8. RagB was shown to be a TLR2 and TLR4 agonist that activated STAT4 and NFκB transcription factors. ΔragB mutants also induced a reduced inflammatory response compared to the wild type strain as well as reduced survivability when exposed to oral epithelial cells which adds evidence to the role of ragB in epithelial cell colonization. These results suggest that ragB elicits a major pro-inflammatory response in primary human monocytes and therefore could play an important role in the etiology of periodontitis and systemic sequelae.

Download

Share

COinS