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.

Life Below the Gum Line: Pathogenic Mechanisms of Porphyromonas gingivalis

The strategies used by bacterial pathogens to establish and maintain themselves in the host represent one of the fundamental aspects of microbial pathogenesis. Characterization of these strategies and the underlying molecular machinery offers new opportunities both to our understanding of how organisms cause disease in susceptible individuals and to the development of novel therapeutic measures designed to undermine or interfere with these determinants of successful survival. With respect to the microbial aetiology of the periodontal diseases, a growing body of evidence suggests that the proteolytic enzymes of Porphyromonas gingivalis represent key survival and, by extrapolation, virulence determinants of this periodontal bacterium. This in turn has led to international efforts to characterize these enzymes at the gene and protein level. Approximately 20 protease genes of P. gingivalis with different names and accession numbers have been deposited in the gene databases and a correspondingly heterogeneous nomenclature system is employed for the products of these genes in the literature. However, it is evident, through comparison of these gene sequences and through gene inactivation studies, that the genetic structure of the proteases of this organism, particularly those with specificity for arginyl and lysyl peptide bonds, is less complicated than originally thought. The major extracellular and surface associated arginine specific protease activity is encoded by 2 genes which we recommend be designated rgpA and rgpB (arg-gingipains A & B). Similarly we recommend that the gene encoding the major lysine specific protease activity is designated kgp (lys-gingipain). These three genes, which account for all the extracellular/surface arginine and lysine protease activity in P. gingivalis, belong to a family of sequence-related proteases and haemagglutinins.

Molecular genetics and nomenclature of proteases of Porphyromonas gingivalis

Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with the initiation and progression of adult periodontal disease. Iron is utilized by this pathogen in the form of heme and has been shown to play an essential role in its growth and virulence. Recently, considerable attention has been given to the characterization of various secreted and surface-associated proteins of P. gingivalis and their contribution to virulence. In particular, the properties of proteins involved in the uptake of iron and heme have been extensively studied. Unlike other Gram-negative bacteria, P. gingivalis does not produce siderophores. Instead it employs specific outer membrane receptors, proteases (particularly gingipains), and lipoproteins to acquire iron/heme. In this review, we will focus on the diverse mechanisms of iron and heme acquisition in P. gingivalis. Specific proteins involved in iron and heme capture will be described. In addition, we will discuss new genes for iron/heme utilization identified by nucleotide sequencing of the P. gingivalis W83 genome. Putative iron- and heme-responsive gene regulation in P. gingivalis will be discussed. We will also examine the significance of heme/hemoglobin acquisition for the virulence of this pathogen.

Iron and heme utilization in Porphyromonas gingivalis.

Comparative Properties of Two Cysteine Proteinases (Gingipains R), the Products of Two Related but Individual Genes ofPorphyromonas gingivalis

The cysteine proteases of Porphyromonas gingivalis are extracellular products of an important etiological agent in periodontal diseases. Many of the in vitro actions of these enzymes are consistent with the observed deregulated inflammatory and immune features of the disease. They are significant targets of the immune responses of affected individuals and are viewed by some as potential molecular targets for therapeutic approaches to these diseases. Furthermore, they appear to represent a complex group of genes and protein products whose transcriptional and translational control and maturation pathways may have a broader relevance to virulence determinants of other persistent bacterial pathogens of human mucosal surfaces. As a result, the genetics, chemistry, and virulence-related properties of the cysteine proteases of P. gingivalis have been the focus of much research effort over the last ten years. In this review, we describe some of the progress in their molecular characterization and how their putative biological roles, in relation to the in vivo growth and survival strategies of P. gingivalis, may also contribute to the periodontal disease process.

Cysteine proteases of Porphyromonas gingivalis.

Porphyromonas gingivalis hemagglutinating cysteine proteinases (gingipains) are considered as important virulence factors in the development of adult periodontitis. Using Southern blot analysis it was determined that genes of three distinct but related gingipains (gingipain-R1, gingipain-R2 and gingipain-K) were present in all tested strains including HG66, ATCC 33277, W50, E-20-1, EM-3, 381, A7436, and IKG5, with a region encoding a part of the hemagglutinin domain of gingipain-R1 and gingipain-K showing considerable variability. In contrast, the loci encoding gingipain-R1 (rgp1) and gingipain-R2 (rgp2) were strongly conserved excluding the concurrent occurrence of other gingipain-R-like genes such as cpgR and agp. Significantly, no evidence could be found to support the expression of a gene coding for the putative proteinase porphypain, an enzyme suggested to have both gingipain-R and gingipain-K activity.

Genetic Variation of Porphyromonas gingivalis Genes Encoding Gingipains, Cysteine Proteinases with Arginine or Lysine Specificity

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Genetic Variation of Porphyromonas gingivalis Genes Encoding Gingipains, Cysteine Proteinases with Arginine or Lysine Specificity