Breaking bad: manipulation of the host response by Porphyromonas gingivalis

Abstract

Recent metagenomic and mechanistic studies are consistent with a new model of periodontal pathogenesis. This model proposes that periodontal disease is initiated by a synergistic and dysbiotic microbial community rather than by a select few bacteria traditionally known as "periopathogens." Low-abundance bacteria with community-wide effects that are critical for the development of dysbiosis are now known as keystone pathogens, the best-documented example of which is Porphyromonas gingivalis. Here, we review established mechanisms by which P. gingivalis interferes with host immunity and enables the emergence of dysbiotic communities. We integrate the role of P. gingivalis with that of other bacteria acting upstream and downstream in pathogenesis. Accessory pathogens act upstream to facilitate P. gingivalis colonization and co-ordinate metabolic activities, whereas commensals-turned pathobionts act downstream and contribute to destructive inflammation. The recent concepts of keystone pathogens, along with polymicrobial synergy and dysbiosis, have profound implications for the development of therapeutic options for periodontal disease.

Keywords: Dysbiosis; Immune subversion; Inflammation; P. gingivalis; Periodontitis.

Conflict of interest statement

Conflicts of interest. The authors declare no financial or commercial conflict of interest.

© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figures

Figure 1. P. gingivalis interactions with gingival epithelial cells (GECs)

Internalization of P. gingivalis is initiated by binding and activation of β1-integrin receptors on the GEC surface mediated by the FimA fimbriae. P. gingivalis secretes the serine phosphatase SerB, which can enter host cells and activate the actin-depolymerizing molecule cofilin by dephosphorylating the Ser 3 residue. The resulting transient and localized disruption of actin structure allows entry of the organism into the cytoplasm. Integrin-dependent signaling through FAK and paxillin (PXN) also converges on the actin cytoskeleton, inducing a later and more long-lasting subcortical condensed microfilament arrangement. Intracellular P. gingivalis secretes SerB which dephosphorylates the Ser 536 residue of the p65 subunit of NF-κB, thus preventing nuclear translocation of p65 homodimers of NF-κB and suppressing CXCL8 (IL-8) production. Levels of Stat1 are diminished by P. gingivalis which reduce the activity of IFN regulatory factor 1 (IRF1) and downregulate CXCL10 (IP-10) synthesis. Decreased secretion of the neutrophil chemokine CXCL8 and the T-cell chemokine CXCL10 from GECs is called localized chemokine paralysis. Internalized P. gingivalis activates the JAK1-Stat3 and PI3K-Akt pathways thereby suppressing apoptosis. P. gingivalis increases the levels of a number of microRNAs within GECs. miR-105 suppresses TLR2 production, and miR-203 inhibits SOCS3 and elevates Stat3 production.

Figure 2. Synergistic and antagonistic interactions between P. gingivalis and oral streptococci

(A) P. gingivalis fimbrial adhesins FimA and Mfa1 engage the S. gordonii adhesins GAPDH and SspA/B, respectively, and the two species accumulate into a heterotypic community. Mfa1 binding activates a signal transduction cascade within P. gingivalis based on protein tyrosine (de)phosphorylation. Ultimately expression of Mfa1 is downregulated and community development is constrained. Production and activity of P. gingivalis proteases is elevated and the heterotypic community has enhanced pathogencity in bone loss models in vivo. (B) Contact of the P. gingivalis FimA fimbriae with arginine deiminase (ArcA) on the surface of S. cristatus results in downregulation of FimA. Consequently P. gingivalis fails to adhere to S. cristatus, colonization is impeded, and P. gingivalis is inversely correlated with S. cristatus in vivo.

Figure 3. Manipulation of complement, TLRs, and their signaling crosstalk by P. gingivalis

P. gingivalis gingipains (Kgp, HRgpA, RgpB) inhibit the classical, lectin, and alternative pathways of complement activation by degrading the central complement component C3. This prevents the deposition of C3b opsonin or the membrane attack complex (MAC) on the bacteria. P. gingivalis protects itself against complement also by using HRgpA to capture the circulating C4b-binding protein (C4BP), a negative regulator of the classical and lectin pathways. P. gingivalis interacts with TLR2 (specifically with the CD14–TLR2–TLR1 signaling complex) and with TLR4. TLR4 activation is prevented by the bacterium’s atypical LPS that can act as a TLR4 antagonist. A subset of TLR2 responses is subverted by P. gingivalis through instigation of signaling crosstalk with complement receptors. By means of its HRgpA and RgpB which release biologically active C5a from C5, P. gingivalis activates the C5a receptor (C5aR) in macrophages and induces intracellular Ca2+ signaling which synergistically enhances the otherwise weak cAMP responses induced by TLR2 activation alone. The resulting activation of protein kinase A (PKA) inactivates glycogen synthase kinase-3β (GSK3β) and inhibits iNOS-dependent intracellular killing (in macrophages). P. gingivalis-activated TLR2 also induces an inside-out signaling pathway, mediated by RAC1, PI3K and cytohesin-1 (CYT1), which transactivates complement receptor-3 (CR3). Activated CR3 binds P. gingivalis and induces ERK1/2 signaling, which in turn selectively downregulates IL-12 p35 and p40 mRNA expression through suppression of IFN regulatory factor 1 (IRF1). This ERK1/2 pathway is also induced downstream of C5aR. Inhibition of IL-12, and secondarily IFN-γ, results in defective immune clearance of P. gingivalis.