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Review
. 2019 Jul 18:9:262.
doi: 10.3389/fcimb.2019.00262. eCollection 2019.

Pathogenesis of Important Virulence Factors of Porphyromonas gingivalis via Toll-Like Receptors

Lu Jia  1 , Nannan Han  1 , Juan Du  1 , Lijia Guo  2 , Zhenhua Luo  1 , Yi Liu  1
Affiliations
Review

Pathogenesis of Important Virulence Factors of Porphyromonas gingivalis via Toll-Like Receptors

Lu Jia et al. Front Cell Infect Microbiol. .

Abstract

Periodontitis is a common intraoral infection and is inextricably linked to systemic diseases. Recently, the regulation between host immunologic response and periodontal pathogens has become a hotspot to explain the mechanism of periodontitis and related systemic diseases. Since Porphyromonas gingivalis (P. gingivalis) was proved as critical periodontal pathogen above all, researches focusing on the mechanism of its virulence factors have received extensive attention. Studies have shown that in the development of periodontitis, in addition to the direct release of virulent factors by periodontal pathogens to destroy periodontal tissues, over-low or over-high intrinsic immune and inflammatory response mediated by Toll-like receptors (TLRs) can lead to more lasting destruction of periodontal tissues. It is very necessary to sort out how various cytopathic factors of P. gingivalis mediate inflammation and immune responses between the host through TLRs so as to help precisely prevent, diagnose, and treat periodontitis in clinic. This review summarizes the role of three most widely studied pathogenic factors produced by P. gingivalis (lipopolysaccharide, gingipains, pili) and their interactions with TLRs at the cellular and molecular level in the progress of periodontitis.

Keywords: Porphyromonas gingivalis; Toll-like receptors; fimbriae; gingipains; lipopolysaccharide; periodontitis; virulence factor.

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Figures

Figure 1
Figure 1
(A) Structure diagram of P. gingivalis-LPS. LPS is composed of lipid A (the conserved inner region without species specificity), core oligosaccharide (the bridge between lipid A and O-polysaccharide), and O-specific polysaccharide (a highly variable outer region) and located on bacterial outer membrane. (B) Contrast different acylation structure of P. gingivalis and E. coli LPS. Lipid A is composed of a phosphorylated β (1-6) D-glucosamine disaccharide backbone and multi-acyl chains acylated by fatty acids at specific positions. P. gingivalis-LPS with tetra-acylated chains is designated as LPS1435/1449 with its molecular weight of 1435 and 1449 Da, while the penta-acylated is named P. gingivalis-LPS1690 with a molecular weight of 1690 Da. The lipid A of E. coli-LPS is hexa-acylated.
Figure 2
Figure 2
Contrast inflammatory signals in human gingival fibroblasts triggered by the different acylation structures of P. gingivalis LPS and E. coli LPS. P.g-LPS1690 upregulates the expression of IL-6 and IL-8, mainly via the MD-2/TLR4-NF-κB pathway. This process seemed to mimic hexa-acylated E. coli-LPS. Both P.g LPS1435/1449 and LPS1690 stimulate increased expression of TLR2, but E. coli LPS did not trigger TLR2. P.g-LPS1435/1449 primarily induced the p38/MAPK signaling pathway with little sensitization of the NF-κB pathway.
Figure 3
Figure 3
Inflammatory signals in human oral keratinocytes triggered by P. gingivalis-LPS heterogeneity. Either tetra-acylated P.g-LPS1435/1449 or penta-acylated LPS1690 downregulated the expression of IL-6 through the MD-2/TLR4-NF-κB pathway. Because MD-1/CD180 complexes negatively mediate the MD-2/TLR4 pathway, the degree of LPS1435/1449 downregulation via increasing MD-1 was more pronounced than that of LPS1690 via reducing MD-1.
Figure 4
Figure 4
Structure of gingipains. Gingipains are divided into Rgp (arginine-dependent gingipain R) and Kgp (lysine-dependent gingipain K). Rgp has been further subdivided into RgpA and RgpB. The molecular weight of RgpA, RgpB and Kgp is 95, 50, and 105 kDa, respectively. Gingipains are primarily made up of the following components: the signal peptide, the N-terminal domain, the catalytic domain (CD), the immunoglobulin superfamily-like domain (IgSF), the hemagglutinin/adhesion (HA) domain, and the C-terminal domain. The structure of RgpB is the simplest without HA domains. RgpA has four HA domains (called RgpAA1 to RgpAA4) located in the middle of the IgSF and C-terminal domain. Kgp also has 3–5 such domains (called KgpAA1 to KgpAA5) in the light of different bacterial strains.
Figure 5
Figure 5
Antibactericidal mechanisms of C5a-TLR2-CXCR4 cross-talk induced by P. gingivalis in macrophages. P. gingivalis pili activated the TLR2-MyD88-dependent pathway and caused a small amount of cAMP production, while C5a-C5aR activation mediated by P. gingivalis gingipain-degradation of C5 synergistically enhances the production of cAMP. The combination of pili and CXCR4 helped maximize cAMP production via C5a-TLR2 cross-talk. The continuous increase in cAMP activated PKA to mediate CREB capturing the limited binding sites of CBP and inhibited NF-κB, thus reducing macrophage-forming NO and destroying the bactericidal function.
Figure 6
Figure 6
Antibactericidal mechanisms of C5a-TLR2 cross-talk induced by P. gingivalis in neutrophils. The C5aR-TLR2 cross-talk activated by P. gingivalis pili induced degradation of MyD88 in neutrophils. Without MyD88, the coassociation of C5aR-TLR2 promoted P. gingivalis infection through activation of the TIRAP-dependent PI3K signaling pathway, not only producing the inflammatory cytokine TNF-α but also blocking RhoA activation and actin polymerization to inhibit the maturation of phagosomes, thus blocking P. gingivalis phagocytosis.
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