While part of a complex biofilm, P. gingivalis is uniquely able to infect the submucosal regions of the human oral mucosa whereupon it associates in situ with the potent antigen presenting cells dendritic cells (DCs) in CP. These DCs form organized immune conjugates with CD4+ T cells, called oral lymphoid foci or OLF. The immunomodulatory functions of DCs in response to P. gingivalis infection is thus of intense interest in our laboratory. P. gingivalis expresses an unusual immunomodulatory LPS and two fimbrial adhesins: the 67 kDa mfa-1 (minor) fimbriae and the 41 kDa fimA (major) fimbriae. Our published studies indicate that the minor fimbriae of P. gingivalis targets the C-type lectin receptor DC- specific ICAM-grabbing non-integrin (DC-SIGN), for entry into DCs. P. gingivalis is taken into as yet unidentified DC-SIGN-rich intracellular compartments in large numbers, where P. gingivalis appear essentially intact and viable. Moreover, the minor fimbriae induce an immunosuppressive cytokine and costimulatory molecule profile in DCs and the DCs induce a Th2 effector response. We have now purified the native minor fimbriae and it appears to be glycosylated and forms fimbrial-like 200 nm strands, revealed by electron microscopy. The major fimbriae also enhance entry of P. gingivalis into DCs, but DC-SIGN is not involved. These DCs produce high levels of IL-12p70, IL-23 and IL-6 and induce strong CD4+ naive T cell proliferation. The T cells in response to major fimbriae appear to be Th17 cells: secreting IL-17 and IFN3. The objectives of this renewal application therefore are to determine the roles of minor and major fimbriae of P. gingivalis in the intracellular fate of P. gingivalis within human DCs (Aim 1), the signaling pathways in DCs activated by P. gingivalis (Aim 2) and the T cell effector responses elicited in DCs by P. gingivalis (Aim 3). The overall goal of these continuing studies is to identify the mechanisms for how this oral mucosal pathogen is able to persist in DCs and modulate DC-mediated immune responses.

Public Health Relevance

Gum disease or periodontal disease is a disease of the supporting tissues of the teeth that results in early tooth loss and has been linked to increased risk for heart disease or stroke. We do not understand why periodontal disease is so difficult to treat successfully. It seems to be a lifelong infection like AIDS or in some cases tuberculosis. We think that this may be due to the ability of the bacterial species Porphyromonas gingivalis to infect the gums and evade or suppress the immune system. Our results suggest it does this by surviving within the white blood cells dendritic cells and suppressing their immune functions. The purpose of this application is to determine how this species is able to persist in dendritic cells and suppress their functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014328-14
Application #
8288024
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2001-02-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
14
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
Georgia Regents University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Miles, Brodie; Zakhary, Ibrahim; El-Awady, Ahmed et al. (2014) Secondary lymphoid organ homing phenotype of human myeloid dendritic cells disrupted by an intracellular oral pathogen. Infect Immun 82:101-11
Miles, Brodie; Abdel-Ghaffar, Khaled A; Gamal, Ahmed Y et al. (2014) Blood dendritic cells: "canary in the coal mine" to predict chronic inflammatory disease? Front Microbiol 5:6
Miles, Brodie; Scisci, Elizabeth; Carrion, Julio et al. (2013) Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen. J Leukoc Biol 94:281-9
Jotwani, Ravi; Moonga, Baljit S; Gupta, Siddharth et al. (2010) Nuclear factor-kappaB p50 subunits in chronic periodontitis and Porphyromonas gingivalis lipopolysaccharide-pulsed dendritic cells. Ann N Y Acad Sci 1192:278-85
Zeituni, Amir E; McCaig, William; Scisci, Elizabeth et al. (2010) The native 67-kilodalton minor fimbria of Porphyromonas gingivalis is a novel glycoprotein with DC-SIGN-targeting motifs. J Bacteriol 192:4103-10
Jotwani, Ravi; Eswaran, Sridhar V K; Moonga, Surinder et al. (2010) MMP-9/TIMP-1 imbalance induced in human dendritic cells by Porphyromonas gingivalis. FEMS Immunol Med Microbiol 58:314-21
Zeituni, Amir E; Jotwani, Ravi; Carrion, Julio et al. (2009) Targeting of DC-SIGN on human dendritic cells by minor fimbriated Porphyromonas gingivalis strains elicits a distinct effector T cell response. J Immunol 183:5694-704
Muthukuru, Manoj; Cutler, Christopher W (2008) Antigen capture of Porphyromonas gingivalis by human macrophages is enhanced but killing and antigen presentation are reduced by endotoxin tolerance. Infect Immun 76:477-85
Cutler, Christopher W; Teng, Yen-Tung A (2007) Oral mucosal dendritic cells and periodontitis: many sides of the same coin with new twists. Periodontol 2000 45:35-50
Muthukuru, Manoj; Cutler, Christopher W (2006) Upregulation of immunoregulatory Src homology 2 molecule containing inositol phosphatase and mononuclear cell hyporesponsiveness in oral mucosa during chronic periodontitis. Infect Immun 74:1431-5

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