Bacterial Virulence Factors that Contribute to Periodontal Pathogenesis

  • Anders JohanssonEmail author
  • Gunnar Dahlén


In this chapter, the role of different microbial virulence factors in relation to the pathogenesis of periodontal diseases is addressed. These factors are molecules produced by pathogens and contribute to their pathogenicity by promoting colonization and affecting host response. The importance of different virulence factors in the life of the oral biofilm and the interplay with the host’s response is exemplified here by two of the major, and most well studied, periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Both of these microbes have great genetic intraspecies diversity and express a number of different virulence factors, which have the capacity to cause imbalance in the host’s response. A. actinomycetemcomitans is the major pathogen in aggressive forms of periodontitis (Fig. 4.1) that affect young individuals, while P. gingivalis is frequently detected in periodontal pockets of individuals with the chronic forms of the disease (Fig. 4.2). However, the role of these two bacteria in periodontal breakdown is still not entirely clear.


  1. 1.
    Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000. 1997;14:9–11.PubMedCrossRefGoogle Scholar
  2. 2.
    Curtis MA, Zenobia C, Darveau D. The relationship of the oral microbiotia to periodontal health and disease. Cell Host Microbe. 2011;10:302–6.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Meyle J, Chapple I. Molecular aspects of the pathogenesis of periodontitis. Periodontol 2000. 2015;68:7–17.CrossRefGoogle Scholar
  4. 4.
    Hajishengallis G, Darveau RP, Curtis MA. The keystone – pathogen hypothesis. Nat Rev Microbiol. 2012;10:717–25.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hajishengallis G, Liang S, Payne MA, Hashim A, Jotwani R, Eskan MA, McIntosh ML, Alsam A, Kirkwood KL, Lambris JD, Darveau RP, Curtis M. Low abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe. 2011;10:497–506.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. Nat Rev Microbiol. 2010;8:481–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Newman Dorland WA. Dorland’s medical dictionary for health consumers. Philadelphia, PA: Saunders; 2007.Google Scholar
  8. 8.
    Casadevall A, Pirofski L-A. Virulence factors and their mechanisms of action: the view from a damage –response framework. J Water Health. 2009;7:1–18.CrossRefGoogle Scholar
  9. 9.
    Marsh PD, Moter A, Devine DA. Dental plaque biofilms: communities, conflicts and control. Periodontol 2000. 2011;55:16–35.PubMedCrossRefGoogle Scholar
  10. 10.
    Marsh PD. Are dental diseases examples of ecological catastrophes? Microbiology. 2003;149:279–94.PubMedCrossRefGoogle Scholar
  11. 11.
    Marsh PD. Dental plaque as a biofilm and a microbial community – implications for health and disease. BMC Oral Health. 2006;6(Suppl 1):e14.CrossRefGoogle Scholar
  12. 12.
    Marsh PD. The commensal microbiota and the development of human disease – an introduction. J Oral Microbiol. 2015;7:e29128.CrossRefGoogle Scholar
  13. 13.
    Socransky SS, Haffajee AD, Cugini MA, Smith C, Ken RI Jr. Microbial complexes in subgingival plaque. J Clin Periodontol. 1998;25:134–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Takahashi N. Oral microbiome metabolism from “who are they” to “what are they doing”. J Dent Res. 2015;94:1628–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Marsh PD, Devine DA. How is the development of dental biofilms influenced by the host? J Clin Periodontol. 2011;38(Suppl 11):28–35.PubMedCrossRefGoogle Scholar
  16. 16.
    Attström R, Schröder HE. Effect of experimental neutropenia on initial gingivitis in dogs. Scand J Dent Res. 1979;87:7–23.PubMedGoogle Scholar
  17. 17.
    Johansson A, Sandström G, Claesson R, Hänström L, Kalfas S. Anaerobic neutrophil-dependent killing of Actinobacillus actinomycetemcomitans in relation to the bacterial leukotoxicity. Eur J Oral Sci. 2000a;108:136–46.PubMedCrossRefGoogle Scholar
  18. 18.
    Singh A. The capsule of Porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagoscytosis, and increase in virulence. Infect Immun. 2011;79:4533–42.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Lina G, Piemont Y, Godall-Gamot F, Bes M, Peter M-O, Gaudochon V, et al. Involvment of Panton-valentine leukocidin-producing Staphylococcus aureus in primary skin infections nd pneumonia. Clin Infect Dis. 1999;29:1128–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Tadepalli S, Stewart GC, Nagaraja TG, Narayanan SK. Human Fusobacterium necrophorum strains have a leukotoxin gene and exhibit leukotoxic activity. J Med Microbiol. 2008;57:225–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Johansson A. Aggregatibacter actinomycetemcomitans leukotoxin: a powerful tool with capacity to cause imbalance in the host inflammatory response. Toxins. 2011;3:242–59.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kachlany SC. Aggregatibacter actinomycetemcomitans leukotoxin: from threat to therapy. J Dent Res. 2010;89:561–70.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Sundqvist G, Carlsson J, Herrmann B, Tärnvik A. Degradation of human immunoglobulins G and M and complement factors C3 and C5 by black-pigmented Bacteroides. J Med Microbiol. 1985;19:85–94.PubMedCrossRefGoogle Scholar
  24. 24.
    Allenspach-Petrzilka GE, Guggenheim B. Bacterial invasion of the periodontium: an important factor in the pathogenesis of periondontitis? J Clin Periodontol. 1983;10:609–17.PubMedCrossRefGoogle Scholar
  25. 25.
    Ji S, Choi YS, Choi Y. Bacteril invasion and persistence: critical events in the pathogenesis of periodontitis? J Periodontol Res. 2015;50:570–85.CrossRefGoogle Scholar
  26. 26.
    Tribble GD, Lamont RJ. Bacterial invasion of epithelial cells and spreading in periodontal tissue. Periodontol 2000. 2010;52:68–83.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Listgarten MA. Electron microscopic observations on the bacterail flora of acute nectrotizing ulcerative gingivitis. J Periodontol. 1965;36:328–39.PubMedCrossRefGoogle Scholar
  28. 28.
    Listgarten MA. Structure of the microbial flora associated with periodontal health and disease in man. A light and electron microscopic study. J Periodontol. 1976;47:1–18.PubMedCrossRefGoogle Scholar
  29. 29.
    Berglundh T, Gislason O, Lekholm U, Sennerby L, Lindhe J. Histopathological observations of human peri-implantitis lesions. J Clin Periodontol. 2004;31:341–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Lux R, Miller JN, Perk NH, Shi W. Motility and chemotaxis in tissue penetration of oral epithelial cell layers by Treponema denticola. Infect Immun. 2001;69:6276–83.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Katz J, Yang QB, Zhang P, et al. Hydrolysis of epithelial junctional proteins by Porphyromonas gingivalis gingipains. Infect Immun. 2002;70:2512–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Rudney JD, Chen R, Zhang G. Streptococci dominate the diverse flora within buccal cells. J Dent Res. 2005a;84:1185–71.Google Scholar
  33. 33.
    Rudney JD, Chen R, Sedgewick GI. Actinobacillus actinomycetemcomitans, Porphyromonas gongivalis and Tannerella forsythensis are components of a polymicrobial flora within human buccal cells. J Dent Res. 2005b;84:59–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Dibart S, Skobe Z, Snapp KR, Socransky SS, Smith CM, Kent R. Identification of bacterial species or in crevicular epithelial cells from healthy and periododntitis. Oral Microbiol Immunol. 1998;13:30–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Madianos PN, Papapanou PN, Nannmark U, Dahlen G, Sandros J. Porphyromonas gingivalis FDC381 multiplies and persists within human oral epithelial cells in vitro. Infect Immun. 1996;64:660–4.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Peterson JW. Chapter 7: Bacterial pathogenesis. In: Baron S, editor. Medical microbiology. 4th ed. Galveston, TX: Univesity of Texas Medical Branch; 1996.Google Scholar
  37. 37.
    Paramonov N, Aduse-Opoku J, Hashim A, Rangarajan M, Curtis MA. Identification of the linkage between A-polysaccharide and the core in the A-lipopolysaccharide of Porphyromonas gingivalis W50. J Bacteriol. 2015;197:1735–46.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Xie H. Biogenesis and function of Porphyromonas gingivalis outer mebrane vesicles. Future Microbiol. 2015;10:1517–27.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    The Human Microbiome Project. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207–14.CrossRefGoogle Scholar
  40. 40.
    Könönen E, Kanervo A, Takala A, Asikainen S, Jousimies-Somer H. Establishment of oral anaerobes during the first year of life. J Dent Res. 1999;78:1634–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Könönen E. Oral colonization by anaerobic bacteria during childhood: role in health and disease. Oral Dis. 1999;5:276–85.Google Scholar
  42. 42.
    Darby I, Curtis M. Microbiology of periodontal disease in children and young adults. Periodontol 2000. 2001;26:33–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Tinoco EMB, Sivakumar M, Preus HR. The distribution and transmission of Actinobacillus actinomycetemcomitans in families with localized juvenile periodontitis. J Clin Periodontol. 1998;25:99–105.PubMedCrossRefGoogle Scholar
  44. 44.
    Yue G, Kaplan JB, Furgang D, Mansfield KG, Fine DH. A second Aggregatibacter actinomycetemcomitans autotransporter adhesin exhibits specificity for buccal epithelial cells in humans and old world primates. Infect Immun. 2007;75:4440–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Teughels W, Kinder Haake S, Sliepen I, Pauwels M, Van Eldere J, Cassiman JJ, Quirynen M. Bacteria interfere with Actinobacillus actinomycetemcomitans colonization. J Dent Res. 2007;86:611–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Pahumunto N, Runangsi P, Wongsuwaniert M, Piwat S, Dahlen G, Teenpaisan R. Aggregatibacter actinomycetemcomitans serotypes and DGGE subtypes in Thai adults with chronic periodontitis. Arch Oral Biol. 2015;60:1789–96.PubMedCrossRefGoogle Scholar
  47. 47.
    Van Winkelhoff AJ, Rijnsburger MC, van der Velden U. Clonal stability of Porphyromonas gingivalis in untreated periodontitis. J Clin Periodontol. 2008;35:674–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Kuboniwa M, Inaba H, Amano A. Genotyping to distinguish microbial pathogenicity in periodontitis. Periodontol 2000. 2010;54:136–59.PubMedCrossRefGoogle Scholar
  49. 49.
    Anaya-Bergman C, Rosato A, Lewis JP. Iron- and hemin-dependent gene expression of Porphyromonas gingivalis. Mol Oral Microbiol. 2015;30:39–61.PubMedCrossRefGoogle Scholar
  50. 50.
    Pahumunto N, Ruangsri P, Wongsuwanlert M, Piwat S, Dahlen G, Teanpaisan R. Virulence of Aggregatibacter actinomycetemcomitans serotypes and DGGE subtypes isolated from chronic adult periodontitis in Thailand. Anaerobe. 2015;36:60–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Socransky SS, Haffajee AD, Goodson JM, Lindhe J. New concepts of destructive periodontal disease. J Clin Periodontol. 1984;11:21–32.PubMedCrossRefGoogle Scholar
  52. 52.
    Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: current concepts. J Periodontol. 1992;63:322–31.PubMedCrossRefGoogle Scholar
  53. 53.
    Hojo K, Nagaoka S, Ohshima T, Maeda N. Biofilm interaction in dental biofilm development. J Dent Res. 2009;88:982–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Slots J. Human viruses in periodontitis. Periodontol 2000. 2010;53:89–110.PubMedCrossRefGoogle Scholar
  55. 55.
    Kinder Haake S, LeBlanc DJ. Chapter 7: Genetics and molecular biology of oral microorganisms. In: Lamont RJ, Burne RA, Lantz MS, LeBlanc DJ, editors. Oral microbiology and immunology. Washington, DC: ASM Press; 2006. p. 125–67.Google Scholar
  56. 56.
    Dahlén G. Microbiology and treatment of dental abscesses and periodontal-endodontic lesions. Periodontol 2000. 2002;28:206–39.PubMedCrossRefGoogle Scholar
  57. 57.
    Ebersole JL, Kesavalu L, Schneider SL, Machen RL, Holt SC. Comparative virulence of periodontopathogens in a mouse model. Oral Dis. 1995;1:115–28.PubMedCrossRefGoogle Scholar
  58. 58.
    Genco CA, Cutler CW, Kapczynski D, Maloney K, Arnold RR. A novel mouse model to study the virulence of and host response to Porphyromonas (Bacteroides) gingivalis. Infect Immun. 1991;59:1255–63.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Sundqvist G, Figdor D, Hänström L, Sörlin S, Sandström G. Phagocytosis and virulence of different strains of Porphyromonas gingivalis. Scand J Dent Res. 1991;99:117–29.PubMedGoogle Scholar
  60. 60.
    Dahlén G, Fabricius L, Holm SE, Möller ÅJR. Interaction within a collection of eight bacterial strains isolated from a monkey dental root canal. Oral Microbiol Immunol. 1987;2:164–70.PubMedCrossRefGoogle Scholar
  61. 61.
    Fabricius L, Dahlen G, Holm SE, Möller ÅJR. Influence of combinations of oral bacteria on the periapical tissues of monkeys. Scand J Dent Res. 1982;90:200–6.PubMedGoogle Scholar
  62. 62.
    Charalampakis G, Dahlen G, Carlén A, Leonhardt Å. Bacterial markers vs clinical markers to predict progression of chronic periodontitis: a 2-yr prospective observational study. Eur J Oral Sci. 2013;121:394–402.PubMedCrossRefGoogle Scholar
  63. 63.
    Lopez R, Dahlen G, Baelum V. Subgingival microbial consortia and the clinical features of periodontitis in adolescents. Eur J Oral Sci. 2011;119:455–62.PubMedCrossRefGoogle Scholar
  64. 64.
    Perez-Chaparro PJ, Goncalves C, Figueiredo LC, Faveri M, Lobao E, Tamashiro N, Duarte P, Feres M. Newly identified pathogens associated with periodontitis: a systematic review. J Dent Res. 2014;93:846–58.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Curtis MA. Periodontal microbiology--the lid's off the box again. J Dent Res. 2014;93:840–2.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hajishengallis G. The inflammophilic character of the periodontitis-associated microbiota. Mol Oral Microbiol. 2014;29:248–57.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Henderson B, Ward JM, Ready D. Aggregatibacter (Actinobacillus) actinomycetemcomitans: a triple A* periodontopathogen? Periodontol 2000. 2010;54:78–105.PubMedCrossRefGoogle Scholar
  68. 68.
    Albandar JM. Aggressive and acute periodontal diseases. Periodontol 2000. 2014;65:7–12.PubMedCrossRefGoogle Scholar
  69. 69.
    Susin C, Haas AN, Albandar JM. Epidemiology and demographics of aggressive periodontitis. Periodontol 2000. 2014;65:27–45.PubMedCrossRefGoogle Scholar
  70. 70.
    Åberg CH, Kwamin F, Claesson R, Dahlén G, Johansson A, Haubek D. Progression of attachment loss is strongly associated with presence of the JP2 genotype of Aggregatibacter actinomycetemcomitans: a prospective cohort study of a young adolescent population. J Clin Periodontol. 2014;41:232–41.CrossRefGoogle Scholar
  71. 71.
    Dahlén G, Claesson R, Aberg CH, Haubek D, Johansson A, Kwamin F. Subgingival bacteria in Ghanaian adolescents with or without progression of attachment loss. J Oral Microbiol. 2014;6:e23977.CrossRefGoogle Scholar
  72. 72.
    Fine DH, Markowitz K, Furgang D, Fairlie K, Ferrandiz J, Nasri C, McKiernan M, Gunsolley J. Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents. J Clin Microbiol. 2007;45:3859–69.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Haubek D, Ennibi OK, Poulsen K, Vaeth M, Poulsen S, Kilian M. Risk of aggressive periodontitis in adolescent carriers of the JP2 clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans in Morocco: a prospective longitudinal cohort study. Lancet. 2007;371:237–42.Google Scholar
  74. 74.
    Monteiro MF, Casati MZ, Taiete T, do Vale HF, Nociti FH Jr, Sallum EA, Silvério KG, Casarin RC. Periodontal clinical and microbiological characteristics in healthy versus generalized aggressive periodontitis families. J Clin Periodontol. 2015;42(10):914–21. [Epub ahead of print]CrossRefGoogle Scholar
  75. 75.
    Könönen E, Müller HP. Microbiology of aggressive periodontitis. Periodontol 2000. 2014;65:46–78.PubMedCrossRefGoogle Scholar
  76. 76.
    Nibali L, Donos N, Henderson B. Periodontal infectogenomics. J Med Microbiol. 2009;58:1269–74.PubMedCrossRefGoogle Scholar
  77. 77.
    Paino A, Ahlstrand T, Nuutila J, Navickaite I, Lahti M, Tuominen H, Välimaa H, Lamminmäki U, Pöllänen MT, Ihalin R. Identification of a novel bacterial outer membrane interleukin-1Β-binding protein from Aggregatibacter actinomycetemcomitans. PLoS One. 2013;8:e70509.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Nikolopoulos GK, Dimou NL, Hamodrakas SJ, Bagos PG. Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls. J Clin Periodontol. 2008;35:754–67.PubMedCrossRefGoogle Scholar
  79. 79.
    Kittichotirat W, Bumgarner RE, Asikainen S, Chen C. Identification of the pangenome and its components in 14 distinct Aggregatibacter actinomycetemcomitans strains by comparative genomic analysis. PLoS One. 2011;6:e22420.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kittichotirat W, Bumgarner RE, Chen C. Evolutionary Divergence of Aggregatibacter actinomycetemcomitans. J Dent Res. 2016;95(1):94–101. [Epub ahead of print]PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Brogan JM, Lally ET, Poulsen K, Kilian M, Demuth DR. Regulation of Actinobacillus actinomycetemcomitans leukotoxin expression: analysis of the promoter regions of leukotoxic and minimally leukotoxic strains. Infect Immun. 1994;62:501–18.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Claesson R, Gudmundson J, Åberg CH, Haubek D, Johansson A. Detection of a 640-bp deletion in the Aggregatibacter actinomycetemcomitans leukotoxin promoter region in isolates from an adolescent of Ethiopian origin. J Oral Microbiol. 2015;7:e26974.CrossRefGoogle Scholar
  83. 83.
    He T, Nishihara T, Demuth DR, Ishikawa I. A novel insertion sequence increases the expression of leukotoxicity in Actinobacillus actinomycetemcomitansclinical isolates. J Periodontol. 1999;70:1261–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Åberg CH, Kelk P, Johansson A. Aggregatibacter actinomycetemcomitans: virulence of its leukotoxin and association with aggressive periodontitis. Virulence. 2015;6:188–95.PubMedCrossRefGoogle Scholar
  85. 85.
    Wahasugui TC, Nakano V, Piazza RM, Avila-Campos MJ. Phenotypic and genotypic features of Aggregatibacter actinomycetemcomitans isolated from patients with periodontal disease. Diagn Microbiol Infect Dis. 2013;75:366–72.PubMedCrossRefGoogle Scholar
  86. 86.
    Fine DH, Kaplan JB, Kachlany SC, Schreiner HC. How we got attached to Actinobacillus actinomycetemcomitans: a model for infectious diseases. Periodontol 2000. 2006;42:114–57.PubMedCrossRefGoogle Scholar
  87. 87.
    Haubek D, Johansson A. Pathogenicity of the highly leukotoxic JP2 clone of Aggregatibacter actinomycetemcomitans and its geographic dissemination and role in aggressive periodontitis. J Oral Microbiol. 2014;6:e23980.CrossRefGoogle Scholar
  88. 88.
    Höglund Åberg C, Haubek D, Kwamin F, Johansson A, Claesson R. Leukotoxic activity of Aggregatibacter actinomycetemcomitans and periodontal attachment loss. PLoS One. 2014;9:e104095.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Kelk P, Claesson R, Hänström L, Lerner UH, Kalfas S, Johansson A. Abundant secretion of bioactive interleukin-1beta by human macrophages induced by Actinobacillus actinomycetemcomitans leukotoxin. Infect Immun. 2005;73:453–8.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Brage M, Holmlund A, Johansson A. Humoral immune response to Aggregatibacter actinomycetemcomitans leukotoxin. J Periodontal Res. 2011;46:170–5.PubMedCrossRefGoogle Scholar
  91. 91.
    Johansson A, Claesson R, Belibasakis G, Makoveichuk E, Hänström L, Olivecrona G, Sandström G, Kalfas S. Protease inhibitors, the responsible components for the serum-dependent enhancement of Actinobacillus actinomycetemcomitans leukotoxicity. Eur J Oral Sci. 2001;109:335–41.PubMedCrossRefGoogle Scholar
  92. 92.
    Johansson A, Claesson R, Hänström L, Kalfas S. Serum-mediated release of leukotoxin from the cell surface of the periodontal pathogen Actinobacillus actinomycetemcomitans. Eur J Oral Sci. 2003;111:209–15.PubMedCrossRefGoogle Scholar
  93. 93.
    Kieselbach T, Zijnge V, Granström E, Oscarsson J. Proteomics of Aggregatibacter actinomycetemcomitans outer membrane vesicles. PLoS One. 2015;10:e0138591.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Peyyala R, Ebersole JL. Multispecies biofilms and host responses: “discriminating the trees from the forest”. Cytokine. 2013;61:15–25.PubMedCrossRefGoogle Scholar
  95. 95.
    Linhartová I, Bumba L, Mašín J, Basler M, Osička R, Kamanová J, Procházková K, Adkins I, Hejnová-Holubová J, Sadílková L, Morová J, Sebo P. RTX proteins: a highly diverse family secreted by a common mechanism. FEMS Microbiol Rev. 2010;34:1076–112.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Sugai M, Kawamoto T, Pérès SY, Ueno Y, Komatsuzawa H, Fujiwara T, Kurihara H, Suginaka H, Oswald E. The cell cycle-specific growth-inhibitory factor produced by Actinobacillus actinomycetemcomitans is a cytolethal distending toxin. Infect Immun. 1998;66:5008–19.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Grasso F, Frisan T. Bacterial Genotoxins: merging the DNA damage response into infection biology. Biomol Ther. 2015;5:1762–82.Google Scholar
  98. 98.
    Lara-Tejero M, Galán JE. A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein. Science. 2000;290:354–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Belibasakis GN, Mattson A, Wang Y, Chen C, Johansson A. Cell cycle arrest of human gingival fibroblasts and periodontal ligament cells by Actinobacillus actinomycetemcomitans: involvement of the cytolethal distending toxin. APMIS. 2004;112:674–85.PubMedCrossRefGoogle Scholar
  100. 100.
    Shenker BJ, Besack D, McKay T, Pankoski L, Zekavat A, Demuth DR. Induction of cell cycle arrest in lymphocytes by Actinobacillus actinomycetemcomitans cytolethal distending toxin requires three subunits for maximum activity. J Immunol. 2005;174:2228–34.PubMedCrossRefGoogle Scholar
  101. 101.
    Belibasakis GN, Brage M, Lagergård T, Johansson A. Cytolethal distending toxin upregulates RANKL expression in Jurkat T-cells. APMIS. 2008;116:499–506.PubMedCrossRefGoogle Scholar
  102. 102.
    Belibasakis GN, Johansson A, Wang Y, Chen C, Kalfas S, Lerner UH. The cytolethal distending toxin induces receptor activator of NF-kappaB ligand expression in human gingival fibroblasts and periodontal ligament cells. Infect Immun. 2005a;73:342–51.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Ando ES, De-Gennaro LA, Faveri M, Feres M, DiRienzo JM, Mayer MPA. Immune response to cytolethal distending toxin of Aggregatibacter actinomycetemcomitans in periodontitis patients. J Periodontal Res. 2010;45:471–80.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Höglund Åberg C, Antonoglou G, Haubek D, Kwamin F, Claesson R, Johansson A. Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression. PLoS One. 2013;8:e65781.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Teng YT, Hu W. Expression cloning of a periodontitis-associated apoptotic effector, cagE homologue, in Actinobacillus actinomycetemcomitans. Biochem Biophys Res Commun. 2003;303:1086–94.PubMedCrossRefGoogle Scholar
  106. 106.
    Teng YT, Zhang X. Apoptotic activity and sub-cellular localization of a T4SS-associated CagE-homologue in Actinobacillus actinomycetemcomitans. Microb Pathog. 2005;38:125–32.PubMedCrossRefGoogle Scholar
  107. 107.
    Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71:635–700.PubMedCrossRefGoogle Scholar
  108. 108.
    Díaz-Zúñiga J, Yáñez JP, Alvarez C, Melgar-Rodríguez S, Hernández M, Sanz M, Vernal R. Serotype-dependent response of human dendritic cells stimulated with Aggregatibacter actinomycetemcomitans. J Clin Periodontol. 2014;41:242–51.PubMedCrossRefGoogle Scholar
  109. 109.
    Page RC, Sims TJ, Engel LD, Moncla BJ, Bainbridge B, Stray J, Darveau RP. The immunodominant outer membrane antigen of Actinobacillus actinomycetemcomitans is located in the serotype-specific high-molecular-mass carbohydrate moiety of lipopolysaccharide. Infect Immun. 1991;59:3451–62.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Belibasakis GN, Johansson A, Wang Y, Chen C, Lagergård T, Kalfas S, Lerner UH. Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin. Cytokine. 2005b;30:56–63.PubMedCrossRefGoogle Scholar
  111. 111.
    Kelk P, Claesson R, Chen C, Sjöstedt A, Johansson A. IL-1beta secretion induced by Aggregatibacter (Actinobacillus) actinomycetemcomitans is mainly caused by the leukotoxin. Int J Med Microbiol. 2008;298:529–41.PubMedCrossRefGoogle Scholar
  112. 112.
    Belibasakis G, Johansson A. Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes. Cytokine. 2012;59:124–30.PubMedCrossRefGoogle Scholar
  113. 113.
    Mysak J, Podzimek S, Sommerova P, Lyuya-Mi Y, Bartova J, Janatova T, Prochazkova J, Duskova J. Porphyromonas gingivalis: major periodontopathic pathogen overview. J Immunol Res. 2014;2014:e476068.CrossRefGoogle Scholar
  114. 114.
    Bostanci N, Belibasakis GN. Porphyromonas gingivalis: an invasive and evasive opportunistic oral pathogen. FEMS Microbiol Lett. 2012;333:1–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Cortelli JR, Aquino DR, Cortelli SC, Fernandes CB, de Carvalho-Filho J, Franco GC, Costa FO, Kawai T. Etiological analysis of initial colonization of periodontal pathogens in oral cavity. J Clin Microbiol. 2008;46:1322–9.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Loos BG, Dyer DW. Restriction fragment length polymorphism analysis of the fimbrillin locus, fimA of Porphyromonas gingivalis. J Dent Res. 1992;71:1173–81.PubMedCrossRefGoogle Scholar
  117. 117.
    Amano A, Kuboniwa M, Nakagawa I, Akiyama S, Morisaki I, Hamada S. Prevalence of specific genotypes of Porphyromonas gingivalis fimA and periodontal health status. J Dent Res. 2000;79:1664–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Jotwani R, Cutler CW. Fimbriated Porphyromonas gingivalis is more efficient than fimbria-deficient P. gingivalis in entering human dendritic cells in vitro and induces an inflammatory Th1 effector response. Infect Immun. 2004;72:1725–32.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Wang M, Liang S, Hosur KB, Domon H, Yoshimura F, Amano A, Hajishengallis G. Differential virulence and innate immune interaction of type 1 and II fimbrial genotypes of Porphyromonas gingivalis. Oral Microbiol Immunol. 2009;24:478–84.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Laine ML, Appelmelk BJ, van Winkelhoff AJ. Prevalence and distribution of six capsular serotypes of Porphyromonas gingivalis in periodontitis patients. J Den Res. 1997;76:1840–4.CrossRefGoogle Scholar
  121. 121.
    Yoshino T, Laine M, van Winkelhoff AJ, Dahlen G. Genotype variation and capsular serotypes of Porphyromonas gingivlis from chronic periodontitis and periodontal abscesses. FEMS Microbiol Lett. 2007;270:75–81.PubMedCrossRefGoogle Scholar
  122. 122.
    Diericks K, Pauweis M, Laine ML, van Eldere J, Cassiman JJ, van Winkelhoff AJ, Van Steenberghe D, Quirynen M. Adhesion of Porphyromonas gingivalis serotypes to pocket epithelium. J Periodontol. 2003;73:844–8.CrossRefGoogle Scholar
  123. 123.
    Guo Y, Nguyen K-A, Potempa J. Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon’s knife to a meat chopper-like brutal degradation of proteins. Periodontol 2000. 2010;54:15–44.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Potempa J, Sroka A, Imamura T, Travis J. Gingipains, the major cysteine proteinases and virulence factors of Porphyromonas gingivalis: structure, function and assembly of multidomain protein complexes. Curr Protein Pept Sci. 2003;4:397–407.PubMedCrossRefGoogle Scholar
  125. 125.
    Haraguchi A, Miura M, Fujise O, Hamachi T, Nishimura F. Porphyromonas gingivalis gingipain is involved in the detachment and aggregation of Aggregatibacter actinomycetemcomitans biofilm. Mol Oral Microbiol. 2014;29:131–43.PubMedCrossRefGoogle Scholar
  126. 126.
    Johansson A, Hänström L, Kalfas S. Inhibition of Actinobacillus actinomycetemcomitans leukotoxicity by bacteria from the subgingival flora. Oral Microbiol Immunol. 2000b;15:218–25.PubMedCrossRefGoogle Scholar
  127. 127.
    Olsen I, Potempa J. Strategies for the inhibition of gingipains for the potential treatment of periodontitis and associated systemic diseases. J Oral Microbiol. 2014;6:e24800.CrossRefGoogle Scholar
  128. 128.
    McGraw WT, Potempa J, Farley D, Travis J. Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun. 1999;67:3248–56.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Wegner N, Wait R, Sroka A, Eick S, Nguyen KA, Lundberg K, Kinloch A, Culshaw S, Potempa J, Venables PJ. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010;62:2662–72.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Rantapää-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, Sundin U, van Venrooij WJ. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Mangat P, Wegner N, Venables PJ, Potempa J. Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis? Arthritis Res Ther. 2010;12:e209.CrossRefGoogle Scholar
  132. 132.
    Gully N, Bright R, Marino V, Marchant C, Cantley M, Haynes D, Butler C, Dashper S, Reynolds E, Bartold M. Porphyromonas gingivalis peptidylarginine deiminase, a key contributor in the pathogenesis of experimental periodontal disease and experimental arthritis. PLoS One. 2014;9:e100838.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Maresz KJ, Hellvard A, Sroka A, Adamowicz K, Bielecka E, Koziel J, Koziel J, Gawron K, Mizgalska D, Marcinska KA, Benedyk M, Pyrc K, Quirke A-M, Jonsson R, Alzabin S, Venables PJ, Nguyen K-A, Mydel P, Potempa J. Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLoS Pathog. 2013;9:e1003627.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Hajishengallis G, Wang M, Bagby GJ, Nelson S. Importance of TLR2 in early innate immune response to acute pulmonary infection with Porphyromonas gingivalis in mice. J Immunol. 2008;181:4141–9.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Bougas K, Ransjö M, Johansson A. Effects of Porphyromonas gingivalis surface-associated material on osteoclast formation. Odontology. 2013;101:140–9.PubMedCrossRefGoogle Scholar
  136. 136.
    Kassem A, Henning P, Lundberg P, Souza PP, Lindholm C, Lerner UH. Porphyromonas gingivalis stimulates bone resorption by enhancing RANKL (receptor activator of NF-κB ligand) through activation of toll-like receptor 2 in osteoblasts. J Biol Chem. 2015;290:20147–58.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Molecular Periodontology, Department of OdontologyUmeå UniversityUmeåSweden
  2. 2.Department of Oral Microbiology and Immunology, Institute of Odontology, Sahlgrenska AcademyUniversity of GothenburgGöteborgSweden

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