Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidylarginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function, hence, PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further, accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes, chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus, PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level. We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD, within the chronic inflammatory environment and immune system stimulation by bacteria- derived """"""""danger signals"""""""", leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity, including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine, which is also a preferential target for PPAD. Hence, this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA;(ii) functional and structural studies of various forms of PPAD;and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus, the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.

Public Health Relevance

Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis, a known periodontal pathogen, is the only known bacterium, which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed, infected periodontal tissues not only contributes to the pathology of periodontitis, but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE022597-02
Application #
8610914
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202
Gawron, K; Bereta, G; Nowakowska, Z et al. (2017) Analysis of mutations in the SOS-1 gene in two Polish families with hereditary gingival fibromatosis. Oral Dis 23:983-989
Schwenzer, Anja; Quirke, Anne-Marie; Marzeda, Anna M et al. (2017) Association of Distinct Fine Specificities of Anti-Citrullinated Peptide Antibodies With Elevated Immune Responses to Prevotella intermedia in a Subgroup of Patients With Rheumatoid Arthritis and Periodontitis. Arthritis Rheumatol 69:2303-2313
Kariu, T; Nakao, R; Ikeda, T et al. (2017) Inhibition of gingipains and Porphyromonas gingivalis growth and biofilm formation by prenyl flavonoids. J Periodontal Res 52:89-96
Wilensky, A; Potempa, J; Houri-Haddad, Y et al. (2017) Vaccination with recombinant RgpA peptide protects against Porphyromonas gingivalis-induced bone loss. J Periodontal Res 52:285-291
Benedyk, Ma?gorzata; Mydel, Piotr Mateusz; Delaleu, Nicolas et al. (2016) Gingipains: Critical Factors in the Development of Aspiration Pneumonia Caused by Porphyromonas gingivalis. J Innate Immun 8:185-98
Widziolek, Magdalena; Prajsnar, Tomasz K; Tazzyman, Simon et al. (2016) Zebrafish as a new model to study effects of periodontal pathogens on cardiovascular diseases. Sci Rep 6:36023
Plaza, Karolina; Kalinska, Magdalena; Bochenska, Oliwia et al. (2016) Gingipains of Porphyromonas gingivalis Affect the Stability and Function of Serine Protease Inhibitor of Kazal-type 6 (SPINK6), a Tissue Inhibitor of Human Kallikreins. J Biol Chem 291:18753-64
Jusko, Monika; Miedziak, Beata; Ermert, David et al. (2016) FACIN, a Double-Edged Sword of the Emerging Periodontal Pathogen Filifactor alocis: A Metabolic Enzyme Moonlighting as a Complement Inhibitor. J Immunol 197:3245-3259
Kharlamova, Nastya; Jiang, Xia; Sherina, Natalia et al. (2016) Antibodies to Porphyromonas gingivalis Indicate Interaction Between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology. Arthritis Rheumatol 68:604-13
Hellvard, Annelie; Zeitlmann, Lutz; Heiser, Ulrich et al. (2016) Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis. Sci Rep 6:31441

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