Porphyromonas gingivalis-host interactions: open war or intelligent guerilla tactics?

Abstract

This review summarizes and discusses virulence mechanisms whereby Porphyromonas gingivalis can persist in the oral cavity. It is proposed that the virulence of P. gingivalis is dependent, at least in part, upon its ability to establish a complex host-pathogen molecular crosstalk which subverts innate immunity. The sophisticated stealth and sabotage tactics used by P. gingivalis may additionally benefit co-habiting organisms occupying the same niche.

Fig. 1. Model of P. gingivalis exploitation of innate immune receptors for undermining host defenses

P. gingivalis is predominantly recognized by the TLR2/1 heterodimer [34]. Through its fimbriae, the pathogen binds CXCR4 which cross-talks with and suppresses the TLR2/1-induced TIRAP/MyD88-mediated antimicrobial pathway [24]. The mechanism involves CXCR4-induced activation of cAMP-dependent protein kinase A (PKA) which suppresses NF-κB activation and induction of proinflammatory cytokines and antimicrobial molecules, such as the inducible nitric oxide synthase (iNOS). These inhibitory effects promote P. gingivalis survival in vitro and in vivo [24]. The CXCR4 mechanism does not however inhibit the P. gingivalis-induced inside-out signaling, which proceeds via phosphatidylinositol 3-kinase (PI3K) and cytohesin-1 and activates the high-affinity conformation of CR3 [18, 37](and unpublished data). Intriguingly, P. gingivalis interacts with activated CR3 and is thereby internalized; this is a relatively safe portal of entry since CR3 is not linked to vigorous microbicidal mechanisms [4, 36]. Moreover, the P. gingivalis-CR3 interaction induces outside-in signaling, which via extracellular signal-related kinase 1/2 (ERK1/2) downregulates IL-12 p35 and p40 mRNA expression [18], possibly through ERK1/2 suppression of IRF-1 and ICSBP transcription factors [31]. At the protein level, the outcome is reduced production of bioactive IL-12 resulting in impaired immune clearance of P. gingivalis in vivo [18].