Porphyromonas gingivalis is a Gram-negative oral anaerobe that is involved in the pathogenesis of periodontitis, an inflammatory disease that destroys the tissues supporting the tooth, eventually leading to tooth loss. Porphyromonas gingivalis has can locally invade periodontal tissues and evade the host defence mechanisms. In doing so, it utilizes a panel of virulence factors that cause deregulation of the innate immune and inflammatory responses. The present review discusses the invasive and evasive strategies of P. gingivalis and the role of its major virulence factors in these, namely lipopolysaccharide, capsule, gingipains and fimbriae. Moreover, the role of P. gingivalis as a 'keystone' biofilm species in orchestrating a host response, is highlighted.

https://www.zora.uzh.ch/id/eprint/63941/1/5_Bostanci_and_Belibasakis_%28FEMS_ML_2012%29_%282%29.pdf

Porphyromonas gingivalis: an invasive and evasive opportunistic oral pathogen

Porphyromonas gingivalis is a Gram-negative oral anaerobe that is involved in the pathogenesis of periodontitis and is a member of more than 500 bacterial species that live in the oral cavity. This anaerobic bacterium is a natural member of the oral microbiome, yet it can become highly destructive (termed pathobiont) and proliferate to high cell numbers in periodontal lesions: this is attributed to its arsenal of specialized virulence factors. The purpose of this review is to provide an overview of one of the main periodontal pathogens—Porphyromonas gingivalis. This bacterium, along with Treponema denticola and Tannerella forsythia, constitute the “red complex,” a prototype polybacterial pathogenic consortium in periodontitis. This review outlines Porphyromonas gingivalis structure, its metabolism, its ability to colonize the epithelial cells, and its influence upon the host immunity.

/pdf/porphyromonas-gingivalis-major-periodontopathic-pathogen-43ora7pq13.pdf

Porphyromonas gingivalis: major periodontopathic pathogen overview.

For almost two decades, the Th1/Th2 paradigm has offered a productive conceptual framework for investigating the pathogenesis of periodontitis. However, as with many other inflammatory diseases, the observed role of T-cell-mediated immunity in periodontitis did not readily fit this model. A new subset of CD4+ T-cells was recently discovered that explains many of the discrepancies in the classic Th1/Th2 model, and has been termed "Th17" based on its secretion of the novel pro-inflammatory cytokine IL-17. The identification of Th17 cells as a novel effector T-cell population compels re-examination of periodontitis in the context of the new subset and its signature cytokines. This review aims to offer a clarifying insight into periodontal pathogenesis under the extended Th1/Th2/Th17 paradigm, and is predicated on the principle that periodontal disease activity is determined by a complex interplay between the immune system and periodontal pathogens. The re-examination of existing periodontal literature and further studies in the light of these new discoveries may help explain how the inflammatory response results in damage to the periodontium while generally failing to control the pathogens. This knowledge is essential for the development of immunomodulatory intervention strategies for fine-tuning the host response to maximize the protective and minimize the destructive aspects of the periodontal host response. Moreover, with the advent of anti-cytokine biologic drugs that target the Th1 and Th17 pathways in autoimmunity, the potential consequences to periodontal disease susceptibility in humans need to be understood.

/pdf/a-new-inflammatory-cytokine-on-the-block-re-thinking-5xaibvogyc.pdf

A New Inflammatory Cytokine on the Block: Re-thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17

The composition of the subgingival bacterial microbiota is a critical determinant in the health status of periodontal tissues. Gram-negative anaerobes such as Porphyromonas gingivalis are well-established periodontal pathogens, and high numbers of these bacteria are found in the subgingival sulcus of patients with chronic periodontitis (43). However, a burgeoning pool of evidence indicates that these organisms have a far more complex relationship with the host than merely as pathogens. Gram-negative anaerobes are frequently present in the oral cavity of periodontally healthy individuals (23, 44, 92, 121, 127, 128, 170), and indeed health is the most common status of the human gingiva despite years of exposure to a large microbial burden. Periodontal organisms thus appear to have co-evolved with their host to maintain an ecologically balanced association whereby minimal harm is inflicted on, or by, either party. Disease will only ensue when this interaction becomes unbalanced, an event that has been termed an ecological catastrophe (83). Organisms such as P. gingivalis may thus be more accurately characterized as accidental, or host-adapted, pathogens.

In the subgingival compartment, epithelial cells represent a major host interface for colonizing organisms; hence, the interaction between gingival epithelial cells and periodontal bacteria will contribute to the success or failure of colonization, and to the maintenance of health or disease in the host. Undeniably, in the case of P. gingivalis, an intricate and multithreaded relationship exists between the organism and gingival epithelial cells, which, under optimal conditions, results in stable cohabitation, with both bacteria and host cells responding and adapting to the presence of their partner to maintain a state of health. In the event that this relationship becomes perturbed, for example because of an increase in bacterial burden or an inappropriate immune response, the periodontal disease process can be initiated (13).

The ability to adapt in response to the host environment is reflected in the genetic diversity found within many species of periodontal bacteria. Bacteria are masters of adaptation, and at the genetic level are able to rapidly modify and share DNA. For example, there are significant levels of genetic variation among P. gingivalis strains, and many studies have linked this genetic variability to virulence potential (7, 14, 18, 38, 67, 85, 108). Genetic variability among strains is common in bacteria with long-term carrier states, possibly arising from the co-evolutionary dynamic of host–pathogen interactions (62, 123). Genetic variation can produce lineages of bacteria with `good or evil' personalities, in that some are more virulent and associated with disease, whereas other strains of the same species behave in a more commensal manner. In this review, we will discuss the current understanding of pathogenic and commensal aspects of bacterial interactions with periodontal tissues, with a specific focus on P. gingivalis intracellular invasion and molecular modulation of host cells.

/pdf/bacterial-invasion-of-epithelial-cells-and-spreading-in-4ec2dwtf5t.pdf

Bacterial invasion of epithelial cells and spreading in periodontal tissue.

Introduction: Cytokines are of major importance in periodontal disease progression. Interleukin-12 (IL-12) stimulates interferon-gamma production by T helper type 1 (Th1) cells while IL-18 induces Th1 responses when present with IL-12 but Th2 responses in the absence of IL-12. IL-1 beta has been correlated with periodontal disease destruction. This study determined the local concentrations of these cytokines in sites of gingivitis and periodontitis. Methods: Gingival crevicular fluid was collected from two sites in each of 10 gingivitis patients and from two gingivitis sites and two periodontitis sites from each of 10 periodontitis patients. Serum samples were also collected. IL-1 beta, biologically active IL-12 p70, the IL-12 p40 subunit and IL-18 concentrations were determined by enzyme-linked immunoabsorbent assay. Results: IL-1 beta and IL-18 concentrations were higher in the gingival crevicular fluid from periodontitis patients than in that from gingivitis patients; IL-18 concentrations were higher than those of IL-1 beta. Very little IL-12, either p40 or p70, was detected in the gingival crevicular fluid samples. In the serum, very low levels of cytokines were found. The level of serum IL-12 p40, however, was higher than in the fluid from periodontitis sites of periodontitis patients. Conclusion: The local production of IL-1 beta and IL-18 in the gingival crevicular fluid increased with increasing inflammation and IL-18 was the predominant cytokine at both gingivitis and periodontitis sites. Very little IL-12 was detected with levels decreasing with increasing inflammation. These results suggest that there is an association between severity of periodontal disease and levels of IL-1, IL-12 and IL-18.

Interleukin-1beta, interleukin-12 and interleukin-18 levels in gingival fluid and serum of patients with gingivitis and periodontitis.

Porphyromonas gingivalis cysteine proteinases (gingipains) have been associated with virulence in destructive periodontitis, a disease process variously considered to represent an unregulated stimulation of either T helper type 1 (Th1)- or Th2-type cells. Critical in maintaining Th1 activity is the response of T lymphocytes to environmental interleukin 12 (IL-12) in the form of up-regulation of gamma interferon (IFN-gamma) production. Here we demonstrate that in the presence or absence of serum, gingipains were able to hydrolyze IL-12 and reduce the IL-12-induced IFN-gamma production from CD4+ T cells. However, the induction of IL-12 receptors on T cells by gingipains did not correlate with the enhancement of IFN-gamma production. The gingipains cleaved IL-12 within the COOH-terminal region of the p40 and p35 subunit chains, which leads to IL-12 inactivity, whereas IL-2 in these assays was not affected. Inactivation of IL-12 by the gingipains could disrupt the cytokine balance or favor Th2 activities in the progression of periodontitis.

Hydrolysis of interleukin-12 by Porphyromonas gingivalis major cysteine proteinases may affect local gamma interferon accumulation and the Th1 or Th2 T-cell phenotype in periodontitis.

Porphyromonas gingivalis cysteine proteinases (gingipains) have been associated with virulence in destructive periodontitis, a disease process that has been linked with Th2 pathways. Critical in maintaining Th2 activity is the response of B lymphocytes to environmental interleukin (IL)-4, a cytokine that also counteracts Th1-cell differentiation. Here we demonstrate that while the gingipains effectively degrade interleukin (IL)-4 under serum-free conditions, limited hydrolysis was observed in the presence of serum even after prolonged incubation. Gingipains up-regulated CD69 expression directly in purified peripheral blood B cell preparations. Further, the induction of IL-4 receptor expression on B cells by gingipains correlates with B cell activation, which is also manifested by a mitogenic response. These results suggest that the gingipains of P. gingivalis act during the early stage of B-cell growth as a competence signal, whereby sensitized B cells might become more responsive to further challenge in the disease-susceptible individual.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2249.2003.02287.x

Enhancement of Th2 pathways and direct activation of B cells by the gingipains of Porphyromonas gingivalis

The crystal structure of the K1 domain, an adhesin module of the lysine gingipain (Kgp) expressed on the cell surface by the periodontopathic anaerobic bacterium, Porphyromonas gingivalis W83, is compared to the previously determined structures of homologues K2 and K3, all three being representative members of the cleaved adhesin domain family. In the structure of K1, the conformation of the most extensive surface loop is unexpectedly perturbed, perhaps by crystal packing, and is displaced from a previously reported arginine-anchored position observed in K2 and K3. This displacement allows the loop to become free to interact with other proteins; the alternate flipped-out loop conformation is a novel mechanism for interacting with target host proteins, other bacteria, or other gingipain protein domains. Further, the K1 adhesin module, like others, is found to be haemolytic in vitro, and so, functions in erythrocyte recognition thereby contributing to the haemolytic function of Kgp. K1 was also observed to selectively bind to haem-albumin with high affinity, suggesting this domain may be involved in gingipain-mediated haem acquisition from haem-albumin. Therefore, it is most likely that all cleaved adhesin domains of Kgp contribute to the pathogenicity of P. gingivalis in more complex ways than simply mediating bacterial adherence.

/pdf/the-lysine-gingipain-adhesin-domains-from-porphyromonas-3wzpsdnkzq.pdf

The lysine gingipain adhesin domains from Porphyromonas gingivalis interact with erythrocytes and albumin: Structures correlate to function.

The present invention provides a non-naturally occurring nucleotide sequence comprising a coding sequence and optionally a non-coding sequence wherein said coding sequence comprises a contiguous sequence of codons that encodes all or part of a polypeptide having hemoglobin receptor (HbR) activity from Porphyromonas ging ivalis. At least one codon within said coding sequence or one nucleotide within non-coding sequence is selected, upon expression, to produce a higher level of the polypeptide having HbR activity in host cell other than P. gingivalis or an in vitro expression system relative to the corresponding naturally occurring HbR nucleotide sequence from P. gingivalis or related organism. The present invention also contemplates methods of making said nucleotide sequence and the use thereof in the manufacture or selection of a medicament for the treatment or prophylaxis of infection by P.gingivalis or related organism in biological environments from where microorganisms acquire iron, heme or porphyrin generally, but not exclusively, for growth.

Expression facilitating nucleotide sequences for hemoglobin receptor activity from porphyromonas gingivalis

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Hydrolysis of interleukin-12 by Porphyromonas gingivalis major cysteine proteinases may affect local gamma interferon accumulation and the Th1 or Th2 T-cell phenotype in periodontitis.

Enhancement of Th2 pathways and direct activation of B cells by the gingipains of Porphyromonas gingivalis

The lysine gingipain adhesin domains from Porphyromonas gingivalis interact with erythrocytes and albumin: Structures correlate to function.

Expression facilitating nucleotide sequences for hemoglobin receptor activity from porphyromonas gingivalis