Porphyromonas gingivalis
Scientific classification
Domain:
Bacteria
Phylum:
Bacteroidota
Class:
Bacteroidia
Order:
Bacteroidales
Family:
Porphyromonadaceae
Genus:
Porphyromonas
Species:
P. gingivalis
Binomial name
Porphyromonas gingivalis
(Coykendall et al. 1980) Shah and Collins 1988

Porphyromonas gingivalis belongs to the phylum Bacteroidota and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar.

It is found in the oral cavity, where it is implicated in periodontal disease,[1] as well as in the upper gastrointestinal tract, the respiratory tract, and the colon. It has been isolated from women with bacterial vaginosis.[2]

Collagen degradation observed in chronic periodontal disease results in part from the collagenase enzymes of this species. It has been shown in an in vitro study that P. gingivalis can invade human gingival fibroblasts and can survive in the presence of antibiotics.[3] P. gingivalis invades gingival epithelial cells in high numbers, in which case both bacteria and epithelial cells survive for extended periods of time. High levels of specific antibodies can be detected in patients harboring P. gingivalis.

P. gingivalis infection has been linked to Alzheimer's disease[4] and rheumatoid arthritis. It contains the enzyme peptidyl-arginine deiminase, which is involved in citrullination.[5] Patients with rheumatoid arthritis have increased incidence of periodontal disease;[6] antibodies against the bacterium are significantly more common in these patients.[7]

P. gingivalis is divided into K-serotypes based upon capsular antigenicity of the various types.[8] These serotypes have been the drivers of observations regarding bacterial cell to cell interactions to the associated serotype-dependent immune response and risk with pancreatic cancer.[9][10]

Genome

The genome of P. gingivalis was described in 2003 revealing 1,990 open reading frames (i.e. protein-coding sequences), encoded by 2,343,479 bp, with an average G+C content of 48.3%.[11] An estimated 463 genes are essential.[12]

Virulence factors

Gingipain

Arg-gingipain (Rgp) and lys-gingipain (Kgp) are endopeptidase enzymes secreted by P. gingivalis. These gingipains serve many functions for the organism, contributing to its survival and virulence.[13]

Arg-gingipains have been found to play a key role in the collection of nutrients for P. gingivalis survival. Rgp degrades large peptides of the host organism to provide the bacterium with an abundant nitrogen and carbon source from human serum albumin.[14] P. gingivalis can also degrade transferrin within host cells which provides the organism with an abundant iron source needed to perform multiple cellular functions.[15]

The gingipains are also responsible for a number of necessary functions related to host invasion and colonization. Rgp gingipains are necessary for adhesion and invasion as they processed precursor proteins of long fimbriae.[15] The P. gingivalis genes encoding RgpA, Kgp, and hemagglutinin A (HagA) were strongly expressed after incubation with T. denticola. The hemagglutinin adhesion domain-containing proteins act to increase adhesive capacities of P. gingivalis with other bacterial species.[16] They are also associated with coordinating the integrity of the biofilm in the developing and maturation phase.[17] Lys- gingipains (Kgp) can bind to immobilized matrix proteins fibrinogen and fibronectin and may have a role in host colonization.[18]

Gingipains also have the ability to degrade multiple signals of the host immune response. They have the ability to cleave subclass 1 and 3 IgG antibodies[19] as well as proinflammatory cytokines such as IL-1β, IL-2, IL-6, TNF-α and IL-8 in regions of high P. gingivalis concentration,[20] impairing host immune response function. Rgp can inhibit IL-2 accumulation in T-cells, which enables it to evade the host adaptive immune response, by modulating T-cell communication and proliferation.[21]

Gingipains are key factors in tissue damage symptoms of periodontitis, which results from the degradation of matrix metalloproteins, collagen, and fibronectin.[15] Degradation of these substrates interferes with interactions between host cells and the extracellular matrix, therefore impeding wound healing and causing destruction of periodontal tissues.[15] Rgp is responsible for eliciting the host inflammatory response via the p38α MAPK transduction pathway. This response likely contributes to the inflammatory nature of periodontitis and is involved in tissue and bone destruction.[14]

Gingipains have been associated with Alzheimer's disease (AD). Gingipains were discovered from TMAs of patients exhibiting AD brain pathology. Both RgpB and Kgp were discovered from hippocampus and cerebral cortex of AD patients and were found to be associated with tau load, a marker for AD pathology and ubiquitin, which accumulates in tau tangles and amyloid beta plaques in AD brain. P. gingivalis 16S rRNA was also discovered in the cerebral cortex and csf of AD brains. Pretreatment with gingipain inhibitors protected neuron cell degradation caused by administration of gingipains in murine model.[4]

Capsular polysaccharide (CPS)

The encapsulated strain of P. gingivalis is much more virulent than the nonencapsulated strain in a mouse abscess model.[22] The capsule is a capsular polysaccharide and when present down regulates cytokine production especially proinflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, indicating host evasion responses.[20][22] However, other studies have found the CPS to elicit host immune responses like PMN migration and dose and time dependent expression of cell migration chemokines like MCP-1, KC, MIP-2 and RANTES in CPS-challenged murine peritoneal macrophages. These conditions are likely to contribute to the inflammatory lesions observed in periodontitis.[23]

Vaccines made from P. gingivalis CPS apparently impair oral bone loss in murine models. These vaccines have been able to elicit potent immune responses such as increased IgM and IgG responses that recognize whole P. gingivalis organisms.[24]

Fimbriae

Fimbriae are appendages involved in cellular attachment and greatly contribute to virulence and are found on many Gram-negative and some Gram-positive bacteria.

P. gingivalis virulence is heavily associated with fimbriae as they have been characterized to be key factors in adhesion, invasion, and colonization. Fimbriae are also responsible for invasion of membrane vesicles into host cells.[15] They were found to bind to cellular α5β1 integrins, which mediated adherence and impaired the homeostatic controls of host cells.[25] Fimbriae were also found to be associated with modulating β2 integrin adhesive activity for uptake by monocytes using the CD14/TLR2/PI3K signaling complex, which may contribute to intracellular evasion tactics by P. gingivalis.[26] P. gingivalis has long fimbriae, short fimbriae, and accessory components, each of which have distinct functions.[17]

Long fimbriae

Long fimbriae (FimA), also known as major fimbriae, are long, peritrichous, filamentous components.[27] They have a role in initial attachment and organization of biofilms, as they act as adhesins that mediate invasion and colonization of host cells contributing to P. gingivalis virulence.[17]

Short fimbriae

Short fimbriae (Mfa1), also known as minor fimbriae, have distinct roles from long fimbriae and are characterized to be essential for cell-cell auto aggregation and recruitment for microcolony formation.[27] Short fimbriae are involved in cell-cell adhesion with other dental commensals. It was found to coadhere and develop biofilm in conjunction with Streptococcus gordonii by interaction with SspB streptococcal surface polypeptide.[28] This interaction may be essential in the invasion of dentinal tubules by P. gingivalis.[29]

Accessory fimbriae

Fim C, D, and E accessory components associate with the main FimA protein and have a role in binding with matrix proteins and interaction with CXC-chemokine receptor 4. Loss of function experiments have confirmed that P. gingivalis mutants deficient for Fim C, D, or E have drastically attenuated virulence.[30]

Evasion of host defenses and immune responses

P. gingivalis has many ways of evading host immune responses which affects its virulence. It does this by using a combination of gingipain proteases, a capsular polysaccharide, induction of host cell proliferation, and the cleavage of chemokines responsible for neutrophil recruitment.[19][31]

Virulent P. gingivalis further modulates leukocyte recruitment by proteolysis of cytokines and chemokines that are secreted by the host cells. The arg-gingipain and lys-gingipains are responsible for this proteolysis. In a study using a mouse model, P. gingivalis was specifically found to down-regulate IL-8 induction, causing delayed neutrophil recruitment. Prevention of neutrophil recruitment may inhibit the clearance of the bacterium from the site of infection allowing for colonization.[31] P. gingivalis is able to evade opsonophagocytosis from PMN’s by using Gingipain K (Kgp) to cleave IgG 1 and 3. This further modulates immune response by impairing signaling.[19] Other studies have found that P. gingivalis can subvert the complement pathway through C5αR and C3αR, which modulates the killing capacity of leukocytes, allowing for uncontrolled bacterial growth.[31][32][33] P. gingivalis was also found to inhibit pro inflammatory and antimicrobial responses in human monocytes and mouse macrophages by fimbrial binding to CXCR4, inducing PKA signaling and inhibiting TLR-2-mediated immune response.[34]

Once in the host cells, P. gingivalis is capable of inhibiting apoptosis by modulating the JAK/Stat pathway that controls mitochondrial apoptotic pathways.[35][17] A proliferative phenotype may be beneficial to the bacterium as it provides nutrients, impairs host cell signaling, and compromises the integrity of the epithelial cell layer, allowing for invasion and colonization.[17]

Ecology

P. gingivalis plays an important role in the onset of chronic adult periodontitis.[36] Though it is found in low abundance in the oral cavity, it causes a microbial shift of the oral cavity, allowing for uncontrolled growth of the commensal microbial community. This leads to periodontitis through the disruption of the host tissue homeostasis and adaptive immune response.[37] After using laser capture microdissection plus qRT-PCR to detect P. gingivalis in human biopsies, colocalization of P. gingivalis with CD4+ T cells was observed.[38] However, the infection mechanism of T cells by P. gingivalis remains unknown.

P. gingivalis has been associated with increasing the virulence of other commensal bacteria in both in vivo and in vitro experiments. P. gingivalis outer membrane vesicles were found to be necessary for the invasion of epithelial cells of Tannerella forsythia.[39] P. gingivalis short fimbriae were found to be necessary for coculture biofilm formation with Streptococcus gordonii.[28] Interproximal and horizontal alveolar bone loss in mouse models are seen in coinfections involving P. gingivalis and Treponema denticola.[40] The role of P. gingivalis in periodontitis is studied using specific pathogen-free mouse models of periodontal infections. In these models, P. gingivalis inoculation causes significant bone loss, which is a significant characteristic of the disease. In contrast, germ free mice inoculated with a P. gingivalis monoinfection incur no bone loss, indicating that P. gingivalis alone cannot induce periodontitis.[31]

See also

References

  1. ↑ Naito M, Hirakawa H, Yamashita A, Ohara N, Shoji M, Yukitake H, et al. (August 2008). "Determination of the genome sequence of Porphyromonas gingivalis strain ATCC 33277 and genomic comparison with strain W83 revealed extensive genome rearrangements in P. gingivalis". DNA Research. 15 (4): 215–25. doi:10.1093/dnares/dsn013. PMC 2575886. PMID 18524787.
  2. ↑ Africa CW, Nel J, Stemmet M (July 2014). "Anaerobes and bacterial vaginosis in pregnancy: virulence factors contributing to vaginal colonisation". International Journal of Environmental Research and Public Health. 11 (7): 6979–7000. doi:10.3390/ijerph110706979. PMC 4113856. PMID 25014248.
  3. ↑ Irshad M, van der Reijden WA, Crielaard W, Laine ML (December 2012). "In vitro invasion and survival of Porphyromonas gingivalis in gingival fibroblasts; role of the capsule". Archivum Immunologiae et Therapiae Experimentalis. 60 (6): 469–76. doi:10.1007/s00005-012-0196-8. PMID 22949096. S2CID 14254746.
  4. 1 2 Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. (January 2019). "Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors". Science Advances. 5 (1): eaau3333. Bibcode:2019SciA....5.3333D. doi:10.1126/sciadv.aau3333. PMC 6357742. PMID 30746447.
  5. ↑ Wegner N, Wait R, Sroka A, Eick S, Nguyen KA, Lundberg K, et al. (September 2010). "Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis". Arthritis and Rheumatism. 62 (9): 2662–72. doi:10.1002/art.27552. PMC 2941529. PMID 20506214.
  6. ↑ Berthelot JM, Le Goff B (December 2010). "Rheumatoid arthritis and periodontal disease". Joint Bone Spine. 77 (6): 537–41. doi:10.1016/j.jbspin.2010.04.015. PMID 20646949.
  7. ↑ Ogrendik M, Kokino S, Ozdemir F, Bird PS, Hamlet S (June 2005). "Serum antibodies to oral anaerobic bacteria in patients with rheumatoid arthritis". MedGenMed. 7 (2): 2. PMC 1681585. PMID 16369381.
  8. ↑ American Academy of Periodontology 2010 In-Service Exam, question A-85
  9. ↑ Michaud DS, Izard J, Wilhelm-Benartzi CS, You DH, Grote VA, Tjønneland A, et al. (December 2013). "Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study". Gut. 62 (12): 1764–70. doi:10.1136/gutjnl-2012-303006. PMC 3815505. PMID 22990306.
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  12. ↑ Hutcherson JA, Gogeneni H, Yoder-Himes D, Hendrickson EL, Hackett M, Whiteley M, et al. (August 2016). "Comparison of inherently essential genes of Porphyromonas gingivalis identified in two transposon-sequencing libraries". Molecular Oral Microbiology. 31 (4): 354–64. doi:10.1111/omi.12135. PMC 4788587. PMID 26358096.
  13. ↑ Sheets SM, Robles-Price AG, McKenzie RM, Casiano CA, Fletcher HM (May 2008). "Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis". Frontiers in Bioscience. 13 (13): 3215–38. doi:10.2741/2922. PMC 3403687. PMID 18508429.
  14. 1 2 Grenier D, Imbeault S, Plamondon P, Grenier G, Nakayama K, Mayrand D (August 2001). "Role of gingipains in growth of Porphyromonas gingivalis in the presence of human serum albumin". Infection and Immunity. 69 (8): 5166–72. doi:10.1128/IAI.69.8.5166-5172.2001. PMC 98614. PMID 11447200.
  15. 1 2 3 4 5 Furuta N, Takeuchi H, Amano A (November 2009). "Entry of Porphyromonas gingivalis outer membrane vesicles into epithelial cells causes cellular functional impairment". Infection and Immunity. 77 (11): 4761–70. doi:10.1128/IAI.00841-09. PMC 2772519. PMID 19737899.
  16. ↑ Meuric V, Martin B, Guyodo H, Rouillon A, Tamanai-Shacoori Z, Barloy-Hubler F, Bonnaure-Mallet M (February 2013). "Treponema denticola improves adhesive capacities of Porphyromonas gingivalis". Molecular Oral Microbiology. 28 (1): 40–53. doi:10.1111/omi.12004. PMID 23194417.
  17. 1 2 3 4 5 Kuboniwa M, Hasegawa Y, Mao S, Shizukuishi S, Amano A, Lamont RJ, Yilmaz O (February 2008). "P. gingivalis accelerates gingival epithelial cell progression through the cell cycle". Microbes and Infection. 10 (2): 122–8. doi:10.1016/j.micinf.2007.10.011. PMC 2311419. PMID 18280195.
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  20. 1 2 Grenier D, Tanabe S (March 2010). "Porphyromonas gingivalis gingipains trigger a proinflammatory response in human monocyte-derived macrophages through the p38α mitogen-activated protein kinase signal transduction pathway". Toxins. 2 (3): 341–52. doi:10.3390/toxins2030341. PMC 3153194. PMID 22069588.
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  27. 1 2 Lin X, Wu J, Xie H (October 2006). "Porphyromonas gingivalis minor fimbriae are required for cell-cell interactions". Infection and Immunity. 74 (10): 6011–5. doi:10.1128/IAI.00797-06. PMC 1594877. PMID 16988281.
  28. 1 2 Park Y, Simionato MR, Sekiya K, Murakami Y, James D, Chen W, et al. (July 2005). "Short fimbriae of Porphyromonas gingivalis and their role in coadhesion with Streptococcus gordonii". Infection and Immunity. 73 (7): 3983–9. doi:10.1128/IAI.73.7.3983-3989.2005. PMC 1168573. PMID 15972485.
  29. ↑ Love RM, McMillan MD, Park Y, Jenkinson HF (March 2000). "Coinvasion of dentinal tubules by Porphyromonas gingivalis and Streptococcus gordonii depends upon binding specificity of streptococcal antigen I/II adhesin". Infection and Immunity. 68 (3): 1359–65. doi:10.1128/IAI.68.3.1359-1365.2000. PMC 97289. PMID 10678948.
  30. ↑ Pierce DL, Nishiyama S, Liang S, Wang M, Triantafilou M, Triantafilou K, et al. (August 2009). "Host adhesive activities and virulence of novel fimbrial proteins of Porphyromonas gingivalis". Infection and Immunity. 77 (8): 3294–301. doi:10.1128/IAI.00262-09. PMC 2715668. PMID 19506009.
  31. 1 2 3 4 Hajishengallis G, Liang S, Payne MA, Hashim A, Jotwani R, Eskan MA, et al. (November 2011). "Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement". Cell Host & Microbe. 10 (5): 497–506. doi:10.1016/j.chom.2011.10.006. PMC 3221781. PMID 22036469.
  32. ↑ Wang M, Liang S, Hosur KB, Domon H, Yoshimura F, Amano A, Hajishengallis G (December 2009). "Differential virulence and innate immune interactions of Type I and II fimbrial genotypes of Porphyromonas gingivalis". Oral Microbiology and Immunology. 24 (6): 478–84. doi:10.1111/j.1399-302X.2009.00545.x. PMC 2883777. PMID 19832800.
  33. ↑ Liang S, Krauss JL, Domon H, McIntosh ML, Hosur KB, Qu H, et al. (January 2011). "The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss". Journal of Immunology. 186 (2): 869–77. doi:10.4049/jimmunol.1003252. PMC 3075594. PMID 21149611.
  34. ↑ Hajishengallis G, Wang M, Liang S, Triantafilou M, Triantafilou K (September 2008). "Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function". Proceedings of the National Academy of Sciences of the United States of America. 105 (36): 13532–7. Bibcode:2008PNAS..10513532H. doi:10.1073/pnas.0803852105. PMC 2533224. PMID 18765807.
  35. ↑ Mao S, Park Y, Hasegawa Y, Tribble GD, James CE, Handfield M, et al. (August 2007). "Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis". Cellular Microbiology. 9 (8): 1997–2007. doi:10.1111/j.1462-5822.2007.00931.x. PMC 2886729. PMID 17419719.
  36. ↑ Hajishengallis G (2009). "Porphyromonas gingivalis-host interactions: open war or intelligent guerilla tactics?". Microbes and Infection. 11 (6–7): 637–45. doi:10.1016/j.micinf.2009.03.009. PMC 2704251. PMID 19348960.
  37. ↑ Darveau RP, Hajishengallis G, Curtis MA (September 2012). "Porphyromonas gingivalis as a potential community activist for disease". Journal of Dental Research. 91 (9): 816–20. doi:10.1177/0022034512453589. PMC 3420389. PMID 22772362.
  38. ↑ Guyodo H, Meuric V, Le Pottier L, Martin B, Faili A, Pers JO, Bonnaure-Mallet M (March 2012). "Colocalization of Porphyromonas gingivalis with CD4+ T cells in periodontal disease". FEMS Immunology and Medical Microbiology. 64 (2): 175–83. doi:10.1111/j.1574-695x.2011.00877.x. PMID 22066676.
  39. ↑ Inagaki S, Onishi S, Kuramitsu HK, Sharma A (September 2006). "Porphyromonas gingivalis vesicles enhance attachment, and the leucine-rich repeat BspA protein is required for invasion of epithelial cells by "Tannerella forsythia"". Infection and Immunity. 74 (9): 5023–8. doi:10.1128/IAI.00062-06. PMC 1594857. PMID 16926393.
  40. ↑ Verma RK, Rajapakse S, Meka A, Hamrick C, Pola S, Bhattacharyya I, et al. (2010). "Porphyromonas gingivalis and Treponema denticola Mixed Microbial Infection in a Rat Model of Periodontal Disease". Interdisciplinary Perspectives on Infectious Diseases. 2010: 605125. doi:10.1155/2010/605125. PMC 2879544. PMID 20592756.
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