Virulence mechanisms used in the pathogenesis of periodontal diseases caused by Porphyromonas gingivalis
Michał Śmiga 1 , Paulina Ślęzak 1 , Klaudia Siemińska 1 , Teresa Olczak 1Abstract
Periodontal diseases are characterized by progressive inflammation that destroys the tooth-supporting tissues, leading to gum bleeding and tooth loss. Porphyromonas gingivalis is considered one of the main etiological agents responsible for the initiation and progression of chronic periodontitis. This gram-negative, anaerobic bacterium is a part of a multi-species oral biofilm. P. gingivalis does not have the full pathway of protoporphyrin IX synthesis, nor does it produce siderophores. Therefore, for survival and proliferation, it requires heme as a source of iron and protoporphyrin IX. In order to obtain heme, P. gingivalis uses a number of mechanisms that affect the ability of this bacterium to initiate a pathological condition. This review presents the current knowledge regarding the best-known and characterized systems involved in heme acquisition by P. gingivalis. We focused on processes occurring in the initial states of infection, where gingipain, hemagglutinins, and hemolysins play a crucial role. The mechanisms encoded by hmu, iht and hus operons, including proteins with hemophore-like properties, as well as TonB-dependent outer membrane receptors are described. We present their function and participation in the progression of the infection. In addition, we describe mechanisms produced by P. gingivalis and other periodontopathogens in synergistic processes promoting the growth and virulence of P. gingivalis. We also describe processes regulating iron and heme homeostasis, including the homolog of the Fur protein, the two-component system HaeSR, as well as the OxyR, SigH, and PgDps proteins.
References
- 1. Adams P.A., Berman M.C.: Kinetics and mechanism of the interactionbetween human serum albumin and monomeric haemin.Biochem. J., 1980; 191: 95–102
Google Scholar - 2. Anaya-Bergman C., Rosato A., Lewis J.P.: Iron- and hemin-dependentgene expression of Porphyromonas gingivalis. Mol. Oral Microbiol.,2015; 30: 39–61
Google Scholar - 3. Benedyk M., Byrne D.P., Glowczyk I., Potempa J., Olczak M., OlczakT., Smalley J.W.: Pyocyanin, a contributory factor in haem acquisitionand virulence enhancement of Porphyromonas gingivalis in thelung. PLoS One, 2015; 11: e0148008
Google Scholar - 4. Bielecki M., Antonyuk S., Strange R.W., Siemińska K., Smalley J.W.,Mackiewicz P., Śmiga M., Cowan M., Capper M.J., Ślęzak P., Olczak M.,Olczak T.: Prevotella intermedia produces two proteins homologous toPorphyromonas gingivalis HmuY but with different heme coordinationmode. Biochem J., 2020; 477: 381–405
Google Scholar - 5. Bielecki M., Antonyuk S., Strange R.W., Smalley J.W., MackiewiczP., Śmiga M., Stępień P., Olczak M., Olczak T.: Tannerella forsythiaTfo belongs to Porphyromonas gingivalis HmuY-like family ofproteins but differs in heme-binding properties. Biosci. Rep., 2018;38: BSR20181325
Google Scholar - 6. Blasco-Baque V., Garidou L., Pomié C., Escoula Q., Loubieres P., LeGall-David S., Lemaitre M., Nicolas S., Klopp P., Waget A., Azalbert V.,Colom A., Bonnaure-Mallet M., Kemoun P., Serino M., Burcelin R.:Periodontitis induced by Porphyromonas gingivalis drives periodontalmicrobiota dysbiosis and insulin resistance via an impaired adaptiveimmune response. Gut, 2017; 66: 872–885
Google Scholar - 7. Bostanci N., Belibasakis G.N.: Porphyromonas gingivalis: An invasiveand evasive opportunistic oral pathogen. FEMS Microbiol.Lett., 2012; 333: 1–9
Google Scholar - 8. Brown J.L., Yates E.A., Bielecki M., Olczak T., Smalley J.W.: Potentialrole for Streptococcus gordonii-derived hydrogen peroxide inheme acquisition by Porphyromonas gingivalis. Mol. Oral Microbiol.,2018; 33: 322–335
Google Scholar - 9. Butler C., Mitchell H., Dashper S., Reynolds E.: The Porphyromonasgingivalis ferric uptake regulator orthologue does not regulate ironhomeostasis. Genom Data, 2015; 5: 167–168
Google Scholar - 10. Byrne D.P., Manandhar S.P., Potempa J., Smalley J.W.: Break downof albumin and haemalbumin by the cysteine protease interpain A,an albuminase of Prevotella intermedia. BMC Microbiol., 2015; 15: 185
Google Scholar - 11. Byrne D.P., Potempa J., Olczak T., Smalley J.W.: Evidence of mutualismbetween two periodontal pathogens: Co-operative haemacquisition by the HmuY haemophore of Porphyromonas gingivalisand the cysteine protease interpain A (InpA) of Prevotella intermedia.Mol. Oral Microbiol., 2013; 28: 219–229
Google Scholar - 12. Carvalho-Filho P.C., Gomes-Filho I.S., Meyer R., Olczak T., XavierM.T., Trindade S.C.: Role of Porphyromonas gingivalis HmuY inimmunopathogenesis of chronic periodontitis. Mediators Inflamm.,2016; 2016: 7465852
Google Scholar - 13. Castro S.A., Collighan R., Lambert P.A., Dias I.H., Chauhan P.,Bland C.E., Milic I., Milward M.R., Cooper P.R., Devitt A.: Porphyromonasgingivalis gingipains cause defective macrophage migrationtowards apoptotic cells and inhibit phagocytosis of primary apoptoticneutrophils. Cell Death Dis., 2017; 8: e2644
Google Scholar - 14. Chistiakov D.A., Orekhov A.N., Bobryshev Y.V.: Links between atheroscleroticand periodontal disease. Exp. Mol. Pathol., 2016; 100: 220–235
Google Scholar - 15. Ciuraszkiewicz J., Śmiga M., Mackiewicz P., Gmiterek A., BieleckiM., Olczak M., Olczak T.: Fur homolog regulates Porphyromonas gingivalisvirulence under low-iron/heme conditions through a complexregulatory network. Mol. Oral Microbiol., 2014; 29: 333–353
Google Scholar - 16. Contreras H., Chim N., Credali A., Goulding C.W.: Heme uptakein bacterial pathogens. Curr. Opin. Chem. Biol., 2014; 19: 34–41
Google Scholar - 17. Curtis M.A., Sterne J.A., Price S.J., Griffiths G.S., Coulthurst S.K., WiltonJ.M., Johnson N.W.: The protein composition of gingival crevicularfluid sampled from male adolescents with no destructive periodontitis:Baseline data of a longitudinal study. J. Periodontal. Res., 1990; 25: 6–16
Google Scholar - 18. Darveau R.P., Hajishengallis G., Curtis M.A.: Porphyromonas gingivalisas a potential community activist for disease. J. Dent. Res.,2012; 91: 816–820
Google Scholar - 19. Dashper S.G., Hendtlass A., Slakeski N., Jackson C., Cross K.J.,Brownfield L., Hamilton R., Barr I., Reynolds E.C.: Characterizationof a novel outer membrane hemin-binding protein of Porphyromonasgingivalis. J. Bacteriol., 2000; 182: 6456–6462
Google Scholar - 20. Dashper S.G., O’Brien-Simpson N.M., Bhogal P.S., FranzmannA.D., Reynolds E.C.: Purification and characterization of a putativefimbrial protein/receptor of Porphyromonas gingivalis. Aust. Dent.J., 1998; 43: 99–104
Google Scholar - 21. Deng Z.L., Sztajer H., Jarek M., Bhuju S., Wagner-Döbler I.: Worldsapart- transcriptome profiles of key oral microbes in the periodontalpocket compared to single laboratory culture reflect synergisticinteractions. Front. Microbiol., 2018; 9: 124
Google Scholar - 22. de Pablo P., Chapple I.L., Buckley C.D., Dietrich T.: Periodontitis insystemic rheumatic diseases. Nat. Rev. Rheumatol., 2009; 5: 218–224
Google Scholar - 23. Dominy S.S., Lynch C., Ermini F., Benedyk M., Marczyk A., KonradiA., Nguyen M., Haditsch U., Raha D., Griffin C., Holsinger L.J.,Arastu-Kapur S., Kaba S., Lee A., Ryder M.I. i wsp.: Porphyromonasgingivalis in Alzheimer’s disease brains: Evidence for disease causationand treatment with small-molecule inhibitors. Sci. Adv., 2019;5: eaau3333
Google Scholar - 24. Eke P.I., Thornton-Evans G.O., Wei L., Borgnakke W.S., Dye B.A.,Genco R.J.: Periodontitis in US adults: National health and nutritionexamination survey 2009–2014. J. Am. Dent. Assoc., 2018; 149:576–588.e6
Google Scholar - 25. El-Awady A., de Sousa Rabelo M., Meghil M.M., Rajendran M.,Elashiry M., Stadler A.F., Foz A.M., Susin C., Romito G.A., Arce R.M.,Cutler C.W.: Polymicrobial synergy within oral biofilm promotesinvasion of dendritic cells and survival of consortia members. NPJBiofilms Microbiomes, 2019; 5: 11
Google Scholar - 26. Enersen M., Nakano K., Amano A.: Porphyromonas gingivalis fimbriae.J. Oral Microbiol., 2013; 5: 10.3402/jom.v5i0.20265
Google Scholar - 27. Fillat M.F.: The FUR (ferric uptake regulator) superfamily: Diversityand versatility of key transcriptional regulators. Arch. Biochem.Biophys., 2014; 546: 41–52
Google Scholar - 28. Frencken J.E., Sharma P., Stenhouse L., Green D., Laverty D., DietrichT.: Global epidemiology of dental caries and severe periodontitis– a comprehensive review. J. Clin. Periodontol., 2017; 44: S94–S105
Google Scholar - 29. Fujise K., Kikuchi Y., Kokubu E., Okamoto-Shibayama K., IshiharaK.: Effect of extracytoplasmic function sigma factors on autoaggregation,hemagglutination, and cell surface properties of Porphyromonasgingivalis. PLoS One, 2017; 12: e0185027
Google Scholar - 30. Gao J.L., Kwan A.H., Yammine A., Zhou X., Trewhella J., HugrassB.M., Collins D.A.T., Horne J., Ye P., Harty D., Nguyen K.A., Gell D.A.,Hunter N.: Structural properties of a haemophore facilitate targetedelimination of the pathogen Porphyromonas gingivalis. Nat. Commun.,2018; 9: 4097
Google Scholar - 31. Gao J.L., Lu Y., Browne G., Yap B.C., Trewhella J., Hunter N.,Nguyen K.A.: The role of heme binding by DNA-protective proteinfrom starved cells (Dps) in the tolerance of Porphyromonas gingivalisto heme toxicity. J. Biol. Chem., 2012; 287: 42243–42258
Google Scholar - 32. Gao J.L., Nguyen K.A., Hunter N.: Characterization of a hemophore-like protein from Porphyromonas gingivalis. J. Biol. Chem., 2010;285: 40028–40038
Google Scholar - 33. Gmiterek A., Kłopot A., Wójtowicz H., Trindade S.C., Olczak M., OlczakT.: Immune response of macrophages induced by Porphyromonasgingivalis requires HmuY protein. Immunobiology, 2016; 221: 1382–1394
Google Scholar - 34. Gmiterek A., Wójtowicz H., Mackiewicz P., Radwan-Oczko M.,Kantorowicz M., Chomyszyn-Gajewska M., Frąszczak M., BieleckiM., Olczak M., Olczak T.: The unique hmuY gene sequence as a specificmarker of Porphyromonas gingivalis. PLoS One, 2013; 8: e67719
Google Scholar - 35. Guo Y., Nguyen K.A., Potempa J.: Dichotomy of gingipains actionas virulence factors: From cleaving substrates with the precision ofa surgeon’s knife to a meat chopper-like brutal degradation of proteins.Periodontol. 2000, 2010; 54: 15–44
Google Scholar - 36. Hajishengallis G., Darveau R.P., Curtis M.A.: The keystone-pathogenhypothesis. Nat. Rev. Microbiol., 2012; 10: 717–725
Google Scholar - 37. Hanioka T., Matsuse R., Shigemoto Y., Ojima M., Shizukuishi S.:Relationship between periodontal disease status and combinationof biochemical assays of gingival crevicular fluid. J. Periodontal.Res., 2005; 40: 331–338
Google Scholar - 38. Hendrickson E.L., Xia Q., Wang T., Lamont R.J., Hackett M.: Pathwayanalysis for intracellular Porphyromonas gingivalis using a strainATCC 33277 specific database. BMC Microbiol., 2009; 9: 185
Google Scholar - 39. Hiratsuka K., Hayakawa M., Kiyama-Kishikawa M., Sasaki Y., HiraiT., Abiko Y.: Role of the hemin-binding protein 35 (HBP35) of Porphyromonasgingivalis in coaggregation. Microb. Pathog., 2008; 44: 320–328
Google Scholar - 40. Holt S.C., Ebersole J.L.: Porphyromonas gingivalis, Treponema denticola,and Tannerella forsythia: The “red complex”, a prototype polybacterialpathogenic consortium in periodontitis. Periodontol.2000, 2005; 38: 72–122
Google Scholar - 41. How K.Y., Song K.P., Chan K.G.: Porphyromonas gingivalis: An overviewof periodontopathic pathogen below the gum line. Front.Microbiol., 2016; 7: 53
Google Scholar - 42. Jung H., Jung S.M., Rim Y.A., Park N., Nam Y., Lee J., Park S. H.,Ju J.H.: Arthritic role of Porphyromonas gingivalis in collagen-inducedarthritis mice. PLoS One, 2017; 12: e0188698
Google Scholar - 43. Kamaguch A., Nakayama K., Ohyama T., Watanabe T., OkamotoM., Baba H.: Coaggregation of Porphyromonas gingivalis and Prevotellaintermedia. Microbiol. Immunol., 2001; 45: 649–656
Google Scholar - 44. Kuboniwa M., Hendrickson E.L., Xia Q., Wang T., Xie H., HackettM., Lamont R.J.: Proteomics of Porphyromonas gingivalis within a modeloral microbial community. BMC Microbiol., 2009; 9: 98
Google Scholar - 45. Kumar R., Lovell S., Matsumura H., Battaile K.P., Moënne-LoccozP., Rivera M.: The hemophore HasA from Yersinia pestis (HasAyp)coordinates hemin with a single residue, Tyr75, and with minimalconformational change. Biochemistry, 2013; 52: 2705–2707
Google Scholar - 46. Lam R.S., O’Brien-Simpson N.M., Holden J.A., Lenzo J.C., FongS.B., Reynolds E.C.: Unprimed, M1 and M2 macrophages differentiallyinteract with Porphyromonas gingivalis. PLoS One, 2016; 11: e0158629
Google Scholar - 47. Lappin D.F., Apatzidou D., Quirke A.M., Oliver-Bell J., ButcherJ.P., Kinane D.F., Riggio M.P., Venables P., McInnes I.B., Culshaw S.:Influence of periodontal disease, Porphyromonas gingivalis and cigarettesmoking on systemic anti-citrullinated peptide antibody titres.J. Clin. Periodontol., 2013; 40: 907–915
Google Scholar - 48. Lasica A.M., Ksiazek M., Madej M., Potempa J.: The type IX secretionsystem (T9SS): Highlights and recent insights into its structureand function. Front. Cell Infect. Microbiol., 2017; 7: 215
Google Scholar - 49. Lewis J.P., Macrina F.L.: IS195, an insertion sequence-like elementassociated with protease genes in Porphyromonas gingivalis. Infect.Immun., 1998: 66: 3035–3042
Google Scholar - 50. Lewis J.P., Plata K., Yu F., Rosato A., Anaya C.: Transcriptionalorganization, regulation and role of the Porphyromonas gingivalisW83 hmu haemin-uptake locus. Microbiology, 2006; 152: 3367–3382
Google Scholar - 51. Li N., Collyer C.A.: Gingipains from Porphyromonas gingivalis –Complex domain structures confer diverse functions. Eur. J. Microbiol.Immunol., 2011; 1: 41–58
Google Scholar - 52. Lira-Junior R., Åkerman S., Klinge B., Boström E.A., GustafssonA.: Salivary microbial profiles in relation to age, periodontal, andsystemic diseases. PLoS One, 2018; 13: e0189374
Google Scholar - 53. Marsh P.D., McDermid A.S., McKee A.S., Baskerville A.: The effectof growth rate and haemin on the virulence and proteolytic activityof Porphyromonas gingivalis W50. Microbiology, 1994; 140: 861–865
Google Scholar - 54. Mesia R., Gholami F., Huang H., Clare-Salzler M., Aukhil I., WalletS.M., Shaddox L. M.: Systemic inflammatory responses in patientswith type 2 diabetes with chronic periodontitis. BMJ Open DiabetesRes. Care, 2016; 4: e000260
Google Scholar - 55. Meuric V., Gracieux P., Tamanai-Shacoori Z., Perez-Chaparro J.,Bonnaure-Mallet M.: Expression patterns of genes induced by oxidativestress in Porphyromonas gingivalis. Oral Microbiol. Immunol.,2008; 23: 308–314
Google Scholar - 56. Moutsopoulos N.M., Kling H.M., Angelov N., Jin W., Palmer R.J.,Nares S., Osorio M., Wahl S.M.: Porphyromonas gingivalis promotesTh17 inducing pathways in chronic periodontitis. J. Autoimmun.,2012; 39: 294–303
Google Scholar - 57. Nazir M.A.: Prevalence of periodontal disease, its association withsystemic diseases and prevention. Int. J. Health Sci., 2017; 11: 72–80
Google Scholar - 58. Nelson K.E., Fleischmann R.D., DeBoy R.T., Paulsen I.T., Fouts D.E.,Eisen J.A., Daugherty S.C., Dodson R.J., Durkin A.S., Gwinn M., HaftD.H., Kolonay J.F., Nelson W.C., Mason T., Tallon L. i wsp.: Completegenome sequence of the oral pathogenic bacterium Porphyromonasgingivalis strain W83. J. Bacteriol., 2003; 185: 5591–5601
Google Scholar - 59. Olczak T.: Analysis of conserved glutamate residues in Porphyromonasgingivalis outer membrane receptor HmuR: Toward a furtherunderstanding of heme uptake. Arch. Microbiol., 2006; 186: 393–402
Google Scholar - 60. Olczak, T., Dixon, D.W., Genco C.A.: Binding specificity of thePorphyromonas gingivalis heme and hemoglobin receptor HmuR, gingipainK, and gingipain R1 for heme, porphyrins, and metalloporphyrins.J. Bacteriol., 2001; 183: 5599–5608
Google Scholar - 61. Olczak T., Simpson W., Liu X., Genco C.A.: Iron and heme utilizationin Porphyromonas gingivalis. FEMS Microbiol. Rev., 2005; 29: 119–144
Google Scholar - 62. Olczak T., Sosicka P., Olczak M.: HmuY is an important virulencefactor for Porphyromonas gingivalis growth in the heme-limited hostenvironment and infection of macrophages. Biochem. Biophys. Res.Commun., 2015; 467: 748–753
Google Scholar - 63. Olczak T., Sroka A., Potempa J., Olczak M.: Porphyromonas gingivalisHmuY and HmuR: Further characterization of a novel mechanismof heme utilization. Arch. Microbiol., 2008; 189: 197–210
Google Scholar - 64. Olczak T., Wójtowicz H., Ciuraszkiewicz J., Olczak M.: Speciesspecificity, surface exposure, protein expression, immunogenicity,and participation in biofilm formation of Porphyromonas gingivalisHmuY. BMC Microbiol., 2010; 10: 134
Google Scholar - 65. Olsen I., Lambris J.D., Hajishengallis G.: Porphyromonas gingivalisdisturbs host-commensal homeostasis by changing complementfunction. J. Oral Microbiol., 2017; 9: 1340085
Google Scholar - 66. Park Y., Simionato M.R., Sekiya K., Murakami Y., James D., ChenW., Hackett M., Yoshimura F., Demuth D.R., Lamont R.J.: Short fimbriaeof Porphyromonas gingivalis and their role in coadhesion withStreptococcus gordonii. Infect. Immun., 2005; 73: 3983–3989
Google Scholar - 67. Petersen P.E., Ogawa H.: The global burden of periodontal disease:Towards integration with chronic disease prevention and control.Periodontol. 2000, 2012; 60: 15–39
Google Scholar - 68. Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., GreenblattD.M., Meng E.C., Ferrin T.E.: UCSF Chimera – a visualization systemfor exploratory research and analysis. J. Comput. Chem., 2004; 25:1605–1612
Google Scholar - 69. Popadiak K., Potempa J., Riesbeck K., Blom A.M.: Biphasic effectof gingipains from Porphyromonas gingivalis on the human complementsystem. J. Immunol., 2007; 178: 7242–7250
Google Scholar - 70. Potempa J., Banbula A., Travis J.: Role of bacterial proteinases inmatrix destruction and modulation of host responses. Periodontol.2000, 2000; 24: 153–192
Google Scholar - 71. Potempa J., Sroka A., Imamura T., Travis J.: Gingipains, the majorcysteine proteinases and virulence factors of Porphyromonas gingivalis:Structure, function and assembly of multidomain protein complexes.Curr. Protein Pept. Sci., 2003; 4: 397–407
Google Scholar - 72. Richard K.L., Kelley B.R., Johnson J.G.: Heme uptake and utilizationby Gram-negative bacterial pathogens. Front. Cell Infect.Microbiol., 2019; 9: 81
Google Scholar - 73. Romero-Lastra P., Sánchez M.C., Llama-Palacios A., Figuero E.,Herrera D., Sanz M.: Gene expression of Porphyromonas gingivalisATCC 33277 when growing in an in vitro multispecies biofilm. PLoSOne, 2019; 14: e0221234
Google Scholar - 74. Rudney J.D., Chen R., Sedgewick G.J.: Actinobacillus actinomycetemcomitans,Porphyromonas gingivalis, and Tannerella forsythensisare components of a polymicrobial intracellular flora within humanbuccal cells. J. Dent. Res., 2005; 84: 59–63
Google Scholar - 75. Scott J.C., Klein B.A., Duran-Pinedo A., Hu L., Duncan M.J.: A twocomponentsystem regulates hemin acquisition in Porphyromonasgingivalis. PLoS One, 2013; 8: e73351
Google Scholar - 76. Sender R., Fuchs S., Milo R.: Revised estimates for the number ofhuman and bacteria cells in the body. PLoS Biol., 2016; 14: e1002533
Google Scholar - 77. Seymour G.J., Ford P.J., Cullinan M.P., Leishman S., Yamazaki K.:Relationship between periodontal infections and systemic disease.Clin. Microbiol. Infect., 2007; 13: 3–10
Google Scholar - 78. Shimotahira N., Oogai Y., Kawada-Matsuo M., Yamada S., FukutsujiK., Nagano K., Yoshimura F., Noguchi K., Komatsuzawa H.: Thesurface layer of Tannerella forsythia contributes to serum resistanceand oral bacterial coaggregation. Infect. Immun., 2013; 81: 1198–1206
Google Scholar - 79. Shoji M., Shibata Y., Shiroza T., Yukitake H., Peng B., Chen Y.Y.,Sato K., Naito M., Abiko Y., Reynolds E.C., Nakayama K.: Characterizationof hemin-binding protein 35 (HBP35) in Porphyromonas gingivalis:Its cellular distribution, thioredoxin activity and role in hemeutilization. BMC Microbiol., 2010; 10: 152
Google Scholar - 80. Singh A., Wyant T., Anaya-Bergman C., Aduse-Opoku J., BrunnerJ., Laine M.L., Curtis M.A., Lewis J.P.: The capsule of Porphyromonasgingivalis leads to a reduction in the host inflammatory response,evasion of phagocytosis, and increase in virulence. Infect. Immun.,2011; 79: 4533–4542
Google Scholar - 81. Smalley J.W., Birss A.J., Szmigielski B., Potempa J.: Sequential actionof R- and K-specific gingipains of Porphyromonas gingivalis in thegeneration of the haem-containing pigment from oxyhaemoglobin.Arch. Biochem. Biophys., 2007; 465: 44–49
Google Scholar - 82. Smalley J.W., Byrne D.P., Birss A.J, Wojtowicz H., Sroka A., PotempaJ., Olczak T.: HmuY haemophore and gingipain proteasesconstitute a unique synthrophic system of haem acquisition by Porphyromonasgingivalis. PLoS One, 2011; 6, e17182
Google Scholar - 83. Smalley J.W., Silver J., Marsh P.J., Birss A.J.: The periodontopathogenPorphyromonas gingivalis binds iron protoporphyrin IX in themu-oxo dimeric form: An oxidative buffer and possible pathogenicmechanism. Biochem. J., 1998; 331: 681–685
Google Scholar - 84. Smalley J.W., Thomas M.F., Birss A.J., Withnall R., Silver J.: A combinationof both arginine- and lysine-specific gingipain activity of Porphyromonasgingivalis is necessary for the generation of the μ-oxo bishaemcontainingpigment from haemoglobin. Biochem. J., 2004; 379: 833–840
Google Scholar - 85. Socransky S.S., Haffajee A.D., Cugini M.A., Smith C., Kent R.L.Jr.:Microbial complexes in subgingival plaque. J. Clin. Periodontol., 1998;25: 134–144
Google Scholar - 86. Sroka A., Sztukowska M., Potempa J., Travis J., Genco C.A.: Degradationof host heme proteins by lysine- and arginine-specific cysteineproteinases (gingipains) of Porphyromonas gingivalis. J. Bacteriol., 2001;183: 5609–5616
Google Scholar - 87. Suzuki N., Yoneda M., Hirofuji T.: Mixed red-complex bacterial infectionin periodontitis. Int. J. Dent., 2013; 2013: 587279
Google Scholar - 88. Szafrański S.P., Deng Z.L., Tomasch J., Jarek M., Bhuju S., MeisingerC., Kühnisch J., Sztajer H., Wagner-Döbler I.: Functional biomarkersfor chronic periodontitis and insights into the roles of Prevotellanigrescens and Fusobacterium nucleatum; A metatranscriptomeanalysis. NPJ Biofilms Microbiomes, 2015; 1: 15017
Google Scholar - 89. Śmiga M., Bielecki M., Olczak M., Olczak T.: Porphyromonas gingivalisPgFur is a member of a novel Fur subfamily with non-canonicalfunction. Front. Cell Infect. Microbiol., 2019; 9: 233
Google Scholar - 90. Śmiga M., Bielecki M., Olczak M., Smalley J.W., Olczak T.: Anti-HmuY antibodies specifically recognize Porphyromonas gingivalisHmuY protein but not homologous proteins in other periodontopathogens.PLoS One, 2015; 10: e0117508
Google Scholar - 91. Śmiga M., Stępień P., Olczak M., Olczak T.: PgFur participatesdifferentially in expression of virulence factors in more virulentA7436 and less virulent ATCC 33277 Porphyromonas gingivalis strains.BMC Microbiol., 2019; 19: 127
Google Scholar - 92. Tolosano E., Altruda F.: Hemopexin: Structure, function, andregulation. DNA Cell Biol., 2002; 21; 297–306
Google Scholar - 93. Trindade S.C., Olczak T., Gomes-Filho I.S., Moura-Costa L.F., CerqueiraE.M., Galdino-Neto M., Alves H., Carvalho-Filho P.C., XavierM.T., Meyer R.: Induction of interleukin (IL)-1β, IL-10, IL-8 and immunoglobulinG by Porphyromonas gingivalis HmuY in humans. J.Periodontal. Res., 2012; 47: 27–32
Google Scholar - 94. Veith P.D., Chen Y.Y., Gorasia D.G., Chen D., Glew M.D., O’Brien-Simpson N.M., Cecil J.D., Holden J.A., Reynolds E.C.: Porphyromonasgingivalis outer membrane vesicles exclusively contain outer membraneand periplasmic proteins and carry a cargo enriched withvirulence factors. J. Proteome Res., 2014; 13: 2420–2432
Google Scholar - 95. Wang R.E., Tian L., Chang Y.H.: A homogeneous fluorescentsensor for human serum albumin. J. Pharm. Biomed. Anal., 2012;63: 165–169
Google Scholar - 96. Widziolek M., Prajsnar T.K., Tazzyman S., Stafford G.P., PotempaJ., Murdoch C.: Zebrafish as a new model to study effects of periodontalpathogens on cardiovascular diseases. Sci. Rep., 2016; 6: 36023
Google Scholar - 97. Wójtowicz H., Guevara T., Tallant C., Olczak M., Sroka A., PotempaJ., Solà M., Olczak T., Gomis-Rüth F.X.: Unique structure andstability of HmuY, a novel heme-binding protein of Porphyromonasgingivalis. PLoS Pathog., 2009; 5: e1000419
Google Scholar - 98. Wójtowicz H., Wojaczyński J., Olczak M., Króliczewski J., Latos-Grazyński L., Olczak T.: Heme environment in HmuY, the hemebindingprotein of Porphyromonas gingivalis. Biochem. Biophys. Res.Commun., 2009; 383: 178–182
Google Scholar - 99. Xie H., Zheng C.: OxyR activation in Porphyromonas gingivalis inresponse to a hemin-limited environment. Infect. Immun., 2012;80: 3471–3480
Google Scholar - 100. Yanamandra S.S., Sarrafee S.S., Anaya-Bergman C., Jones K.,Lewis J.P.: Role of the Porphyromonas gingivalis extracytoplasmicfunction sigma factor, SigH. Mol. Oral Microbiol., 2012; 27: 202–219
Google Scholar - 101. Zhang Y., Wang T., Chen W., Yilmaz O., Park Y., Jung I.Y., HackettM., Lamont R.J.: Differential protein expression by Porphyromonasgingivalis in response to secreted epithelial cell components.Proteomics, 2005; 5: 198–211
Google Scholar - 102. Zhou L.N., Bi C.S., Gao L.N., An Y., Chen F., Chen F.M.: Macrophagepolarization in human gingival tissue in response to periodontaldisease. Oral Dis., 2019; 25: 265–273
Google Scholar - 103. Zhu W., Lee S.W.: Surface interactions between two of the mainperiodontal pathogens: Porphyromonas gingivalis and Tannerella forsythia.J. Periodontal. Implant. Sci., 2016; 46: 2–9
Google Scholar