Life below the gum line: pathogenic mechanisms of Porphyromonas gingivalis

Abstract

Porphyromonas gingivalis, a gram-negative anaerobe, is a major etiological agent in the initiation and progression of severe forms of periodontal disease. An opportunistic pathogen, P. gingivalis can also exist in commensal harmony with the host, with disease episodes ensuing from a shift in the ecological balance within the complex periodontal microenvironment. Colonization of the subgingival region is facilitated by the ability to adhere to available substrates such as adsorbed salivary molecules, matrix proteins, epithelial cells, and bacteria that are already established as a biofilm on tooth and epithelial surfaces. Binding to all of these substrates may be mediated by various regions of P. gingivalis fimbrillin, the structural subunit of the major fimbriae. P. gingivalis is an asaccharolytic organism, with a requirement for hemin (as a source of iron) and peptides for growth. At least three hemagglutinins and five proteinases are produced to satisfy these requirements. The hemagglutinin and proteinase genes contain extensive regions of highly conserved sequences, with posttranslational processing of proteinase gene products contributing to the formation of multimeric surface protein-adhesin complexes. Many of the virulence properties of P. gingivalis appear to be consequent to its adaptations to obtain hemin and peptides. Thus, hemagglutinins participate in adherence interactions with host cells, while proteinases contribute to inactivation of the effector molecules of the immune response and to tissue destruction. In addition to direct assault on the periodontal tissues, P. gingivalis can modulate eucaryotic cell signal transduction pathways, directing its uptake by gingival epithelial cells. Within this privileged site, P. gingivalis can replicate and impinge upon components of the innate host defense. Although a variety of surface molecules stimulate production of cytokines and other participants in the immune response, P. gingivalis may also undertake a stealth role whereby pivotal immune mediators are selectively inactivated. In keeping with its strict metabolic requirements, regulation of gene expression in P. gingivalis can be controlled at the transcriptional level. Finally, although periodontal disease is localized to the tissues surrounding the tooth, evidence is accumulating that infection with P. gingivalis may predispose to more serious systemic conditions such as cardiovascular disease and to delivery of preterm infants.

FIG. 1

Multiple adhesive interactions of P. gingivalis. Adherence mechanisms may vary according to substrate, and adherence may be multimodal. P. gingivalis releases membrane vesicles containing functional adhesins that may also bind to the substrates shown. Compiled from references , , , , , , , , , and .

FIG. 2

Functional domains of P. gingivalis fimbrillin. Numbers refer to amino acid residues. Abbreviations: AG, immunodominant (IgG binding); B Cell, stimulation of B cells; CK, stimulation of cytokines; CT, chemotaxis; FN, binding to fibronectin; LF, binding to lactoferrin; PRP, binding to salivary PRPs; RBC, binding to erythrocytes; STA, binding to salivary statherin; STREP, binding to Streptococcus oralis; T Cell, stimulation of T cells. The boundaries of the domains are not known precisely. Compiled from references , , , , , –, , , and .

FIG. 3

Model of the currently understood P. gingivalis interactions with gingival epithelial cells. Abbreviations: CM, cytoplasmic membrane; MF, actin microfilaments; MT, tubulin microtubules; NM, nuclear membrane; P, phosphate; ; pathway with potential intermediate steps; , translocation; , release; , reversible association. Compiled from references , , , , , , , and .

FIG. 4

P. gingivalis gene products encoding cysteine proteinase activity and/or containing HagA (hemagglutinin)-related sequences. The HagA (GenBank accession no. U41807) precursor comprises 2628 aa and contains four contiguous repeat blocks of 440 to 456 aa each, with >98% identical residues (▨). Sequences within the other proteins shown that are 90% or more identical to the HagA sequence are also indicated by this pattern. All polypeptides carry a putative leader peptide (▩) at the NH₂ terminus. PrpR1 (accession no. X82680) Arg-X-specific proteinase precursor is proteolytically cleaved at the amino acid residues indicated (arrows) to generate α and β species, as described by Rangarajan et al. (210). Culture supernatant proteinase activities are associated with three forms designated RI (αβ), RIA (α), and RIB (*α), shown below PrpR1 and discussed in the text. Homologous proteins to PrpR1, from a number of different P. gingivalis strains, include PrtR (L26341), Rgp-1 (U15282), RgpA (A55426), Agp (D26470), and CpgR (X85186). The P. gingivalis strains examined all contain a second gene encoding an Arg-X proteinase designated Rgp-2 (U85038), RgpB (D64081), and PrtRII (AF007124). Rgp-2 consists of a discrete N-terminal catalytic domain without the associated C-terminal adhesin region (158). Cell surface-associated Arg-X-specific proteinase activity is found as a multimeric complex (18) consisting of five polypeptides derived from cleavage of the polyprotein (shown below PrtR) and four proteolytic products of the Lys-X-specific proteinase shown below PrtP (U42210), also designated PrtK (U75366) or Kgp (1,723 aa) (D83258 and U54691). The HagD (hemagglutinin) sequence begins at aa 364 within PrtP. The Tla protein (Y07618) is a putative outer membrane-associated receptor that, over 795 aa, has 99% identity to the COOH-terminal half of PrtK (PrtP, Kgp). Sequences with 90% or greater identity to HagD are indicated (▨). The patterns of regional sequence similarities amongst the various gene products are far more complex than depicted in this figure, which has been simplified for clarity, and the reader is referred to reference for a detailed comparison of sequence identities between HagA, Rgp-1, and PrtP.