Senior Member of the Staff
Department of Molecular Genetics
P.Gingivalis website
email:
University of Birmingham, UK, B.Sc., 1965, Bacteriology/Immunology
University of Oxford, UK, Ph.D., 1971, Microbiology
Humans live peacefully with billions of microorganisms on and in their bodies. In reality, this benign coexistence is based on a dynamic and delicate equilibrium, the result of millions of years of co-evolution. Tip the balance, and organisms that are normally harmless can become pathogenic. Such a balancing act goes on among the many bacterial species living in the mouth. A change in the environment can upset this harmony, triggering gum disease or tooth decay. How bacteria respond to environmental signals and become pathogenic is a focus of research in the Duncan laboratory.
Porphyromonas gingivalis is a gram-negative oral anaerobe strongly associated with adult periodontitis. We use molecular genetic approaches to identify P. gingivalis genes that determine how the bacterium initiates infection and colonizes host tissue. Three main focus areas are: The role of cysteine proteinases (gingipains) in P. gingivalis adherence and internalization by human epithelial cells; The regulation of genes that encode virulence factors; The cross-talk between P. gingivalis and host cells. Understanding the molecular basis of these interactions is essential for the development of successful intervention therapies and preventive treatments.
The organism interacts with the epithelium lining the gingival sulcus, and in an in vitro model system we investigate adherence of P. gingivalis to human epithelial cells. Using several approaches we showed that gingipain adhesin peptides on the bacterial cell surface bind to epithelial cells, and that individual subpeptide sequences trigger actin-mediated internalization. We are in the process of isolating epithelial cell ligands for specific gingipain peptide components.
Prokaryotes use two-component signal transduction systems to sense and response to environmental changes. We are investigating the molecular mechanisms of these regulatory systems using genetic and biochemical methods and microarray-based expression analyses. So far we have focused on P. gingivalis systems that regulate the expression of fimbriae, known virulence factors, and on the ability of the bacterium to respond to changes in redox conditions, for example during co-culture with epithelial cells.
Current understanding of the pathogen-host paradigm has evolved to be less microbe — or host-centric. That being said, we capitalize on our strengths in bacterial molecular genetics to study host interactions and gene regulation in P. gingivalis, an equal partner in the complex dynamic, and not simply an inert source of effector products. Through understanding these systems we can envision new mechanisms to disrupt the pathogen-host interaction and control infection, such as novel decoy adhesins or receptors. Further analysis of how P. gingivalis responds to and persists during the aerobic challenges of the infectious process will point to new vulnerabilities in its survival strategies.
Duque C, Stipp RN, Wang B, Smith DJ, Höfling JF, Kuramitsu HK, Duncan MJ, Mattos-Graner RO. Down-regulation of GbpB, a component of the VicRK regulon, affects biofilm formation and cell surface characteristics of Streptococcus mutans. Infect Immun. 2010 Nov 15.
Translocation of Porphyromonas gingivalis gingipain adhesin peptide A44 to host mitochondria prevents apoptosis.
Boisvert H, Duncan MJ. Infect Immun. 2010 Aug;78(8):3616-24.
Nishikawa K, Duncan MJ. Histidine kinase-mediated production and autoassembly of Porphyromonas gingivalis fimbriae. 2010. J. Bacteriol. (In Press)
Chen W, Kajiya M, Giro G, Ouhara K, Mackler H E, Mawardi H, Boisvert H, Duncan MJ, Sato K, Kawai T. 2010. Bacteria-derived hydrogen sulfide promotes IL-8 production from epithelial cells. Biochem. Biophys. Res. Commun. (In press)
Boisvert H, Duncan MJ. (2008) Clathrin-dependent entry of a gingipain adhesin peptide and Porphyromonas gingivalis into host cells. Cell Microbiol. 10(12):2538-2552.
Duran-Pinedo AE, Nishikawa K, Duncan MJ. (2007) The RprY response regulator of Porphyromonas gingivalis. Mol Microbiol. 64(4):1061-1074.
Mattos-Graner RO, Porter KA, Smith DJ, Hosogi Y, Duncan MJ. (2006) Functional analysis of glucan binding protein B from Streptococcus mutans. J. Bacteriol. 188 (11):3813-3825.
Davey ME, Duncan MJ. (2006) Enhanced biofilm formation and loss of capsule synthesis: Deletion of a putative glycosyltransferase in Porphyromonas gingivalis. J. Bacteriol. 188(15):5510-5523.
Hosogi Y, Duncan MJ. (2005) Gene expression in Porphyromonas gingivalis after contact with human epithelial cells. Infect. Immun. 73(4):2327-2335.
Ana Duran Pinedo, Ph.D.
Heike Boisvert, Ph.D.
Karthik Krishnan, Ph.D.
