Review: Pathogen-induced inflammation at sites distant from oral infection: bacterial persistence and induction of cell-specific innate immune inflammatory pathways

Abstract

A hallmark of infection with the gram-negative pathogen Porphyromonas gingivalis is the induction of a chronic inflammatory response. P. gingivalis induces a local chronic inflammatory response that results in oral inflammatory bone destruction, which manifests as periodontal disease. In addition to chronic inflammation at the initial site of infection, mounting evidence has accumulated supporting a role for P. gingivalis-mediated periodontal disease as a risk factor for several systemic diseases including, diabetes, preterm birth, stroke, and atherosclerotic cardiovascular disease. A growing number of in vitro studies have demonstrated that P. gingivalis infection stimulates cell activation commensurate with expected responses paralleling inflammatory atherosclerotic-type responses. Furthermore, various mouse models have been used to examine the ability of P. gingivalis to stimulate chronic inflammatory plaque accumulation and recent studies have pointed to a pivotal role for innate immune signaling via the Toll-like receptors in the chronic inflammation associated with P. gingivalis infection. In this review we discuss the pathogen and host cell specificity of these responses and discuss possible mechanisms by which this oral pathogen can induce and maintain a chronic state of inflammation at sites distant from oral infection.

Figure 1

Chronic infection is established in apolipoprotein A-deficient (ApoE^−/−) mice challenged with Porphyromonas gingivalis and Helicobacter pylori, yet only P. gingivalis-infected mice present with acceleration of atherosclerosis. Stomach tissue from representative uninfected (A), H. pylori-infected (B), and P. gingivalis-infected (C) mice reveal that H. pylori-infected mice (n = 8/group) present with submucosal cellular infiltrate (arrow); representative micrographs of Sudan IV staining for lipids (red) on the intimal surface of the aortic arch region from uninfected (D), H. pylori-infected (E), and P. gingivalis-infected (F) mice show increased staining only in P. gingivalis-challenged mice, which was confirmed by morphometric analysis (G). Horizontal line denotes the group median and black circle represents an individual mouse. Serum levels of the proinflammatory cytokine interleukin-1β (IL-1β) as measured by enzyme-linked immunosorbent assay (H); *P < 0.05 by analysis of variance with Dunn’s multiple comparisons; NS = not significantly different; scale bars in A–C = 25 μm, and D–F = 1 mm.

Figure 2

Porphyromonas gingivalis induces human platelet aggregation. (A) P. gingivalis 381 (P.g) or DPG3 (DPG3) at 10⁸ colony-forming units (CFU)/ml, was added to a suspension of human platelets (2 × 10⁸/ml) and stirred continuously for 10 min in a PAP-4 aggregometer. The % aggregation relative to a collagen control is indicated. *P < 0.001 vs. collagen control. (B) P. gingivalis 381 (P.g) or DPG3 (DPG3) (10⁸ CFU/ml) was added to suspensions of human whole blood (final platelet concentration, 2 × 10⁸/ml) and stirred continuously in a whole blood aggregometer and formation of platelet neutrophil aggregates was determined by flow cytometry. Black = no P. gingivalis addition; gray = + P. gingivalis. *P < 0.001 vs. unchallenged.

Figure 3

Model for Porphyromonas gingivalis systemic infection and acceleration of atherosclerosis. 1. Platelets, monocytes, and dendritic cells are depicted in circulation. 2. Monocytes and dendritic cells are depicted in the oral mucosal lesion. Vaccination prevents oral colonization whereas antibiotics decrease the bacterial burden. Platelets, monocytes, dendritic cells, and foam cells are depicted at the atheroma. CAMs, cell adhesion molecules; IFN, interferon; IL, interleukin; Mφ, macrophages; LDL, low-density lipoprotein; PD, periodontal diseases; SE, sulcular epithelium; SRs, scavenger receptors; TNF, tumor necrosis factor; VE, vascular endothelium.