Porphyromonas gingivalis: Difference between revisions

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{{Taxobox
| color = lightgrey
| name = Porphyromonas gingivalis
| regnum = [[Bacteria]]
| phylum = [[Bacteroidetes]]
| classis = [[Bacteroidetes (class)|Bacteroidetes]]
| ordo = [[Bacteroidales]]
| familia = [[Porphyromonadaceae]]
| genus = ''[[Porphyromonas]]''
| species = ''P. gingivalis''
| binomial = ''Porphyromonas gingivalis''
| binomial_authority = (Coykendall et al. 1980) Shah and Collins 1988
}}
__NOTOC__
{{SI}}
{{CMG}}
{{CMG}}
'''Associate Editor In Chief''': Aarti Narayan


==Overview==
==Overview==
'''''Porphyromonas gingivalis''''' belongs to the ''[[Bacteroides]]'' genus and is a non-motile, [[gram-negative]], rod-shaped, [[anaerobic]] [[pathogen]]ic [[bacterium]]. It forms black colonies on [[blood agar]]. It is found in the oral cavity, where it is implicated in certain forms of [[periodontal disease]], as well as the upper [[gastrointestinal tract]], [[respiratory tract]], and in the [[Colon (anatomy)|colon]]. Collagen degradation that is observed in Chronic Periodontal Disease results in part from the collagenase enzymes of this species.
'''''Porphyromonas gingivalis''''' belongs to the phylum [[Bacteroidetes]] and is a nonmotile, [[Gram-negative]], rod-shaped, [[Anaerobic organism|anaerobic]], [[pathogen]]ic [[bacterium]]. It forms black colonies on [[blood agar]].


==P.gingivalis and Rheumatoid arthrits==
It is found in the oral cavity, where it is implicated in certain forms of [[periodontal disease]],<ref>{{Cite journal|author=Naito M, Hirakawa H, Yamashita A, et al. |title=Determination of the Genome Sequence of Porphyromonas gingivalis Strain ATCC 33277 and Genomic Comparison with Strain W83 Revealed Extensive Genome Rearrangements in P. gingivalis |journal=DNA Res. |volume=15 |issue=4 |pages=215–25 |date=August 2008 |pmid=18524787 |doi=10.1093/dnares/dsn013 |url=http://dnaresearch.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18524787 |pmc=2575886}}</ref> as well as the upper [[gastrointestinal tract]], [[respiratory tract]], and in the [[Colon (anatomy)|colon]]. 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 them in the presence of considerable concentrations of antibiotics.<ref>http://www.ncbi.nlm.nih.gov/pubmed/22949096</ref> ''P. gingivalis'' also invades gingival epithelial cells in high numbers, in which cases both bacteria and epithelial cells survive for extended periods of time.
* P.gingivalis is recognized to be a major pathogen in periodontitis and has been associated with [[Rheumatoid arthritis]] in numerous studies.<ref name="pmid20151800">{{cite journal |author=Dissick A, Redman RS, Jones M, ''et al.'' |title=Association of periodontitis with rheumatoid arthritis: a pilot study |journal=[[Journal of Periodontology]] |volume=81 |issue=2 |pages=223–30 |year=2010 |month=February |pmid=20151800 |doi=10.1902/jop.2009.090309 |url=http://www.joponline.org/doi/abs/10.1902/jop.2009.090309?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |accessdate=2012-04-26}}</ref> <ref name="pmid11453241">{{cite journal |author=Mercado FB, Marshall RI, Klestov AC, Bartold PM |title=Relationship between rheumatoid arthritis and periodontitis |journal=[[Journal of Periodontology]] |volume=72 |issue=6 |pages=779–87 |year=2001 |month=June |pmid=11453241 |doi=10.1902/jop.2001.72.6.779 |url=http://www.joponline.org/doi/abs/10.1902/jop.2001.72.6.779%20?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |accessdate=2012-04-26}}</ref> <ref name="pmid16284099">{{cite journal |author=Marotte H, Farge P, Gaudin P, Alexandre C, Mougin B, Miossec P |title=The association between periodontal disease and joint destruction in rheumatoid arthritis extends the link between the HLA-DR shared epitope and severity of bone destruction |journal=[[Annals of the Rheumatic Diseases]] |volume=65 |issue=7 |pages=905–9 |year=2006 |month=July |pmid=16284099 |pmc=1798215 |doi=10.1136/ard.2005.036913 |url=http://ard.bmj.com/cgi/pmidlookup?view=long&pmid=16284099 |accessdate=2012-04-26}}</ref>
High levels of specific antibodies can be detected in patients harboring ''P. gingivalis''.
* It is the only bacteria known to express the peptidylarginine deiminase enzyme(PAD), playing a major role in peptide citrullination.  
*As the anti-cyclic citrullinated peptide antibodies (anti-CCP) are highly specific for [[Rheumatoid arthritis]] and correlate with its severity, the presence of periodontits with P.gingivalis has been thought to be associated with RA.<ref name="pmid10377098">{{cite journal |author=McGraw WT, Potempa J, Farley D, Travis J |title=Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase |journal=[[Infection and Immunity]] |volume=67 |issue=7 |pages=3248–56 |year=1999 |month=July |pmid=10377098 |pmc=116503 |doi= |url=http://iai.asm.org/cgi/pmidlookup?view=long&pmid=10377098 |accessdate=2012-04-26}}</ref>


In addition, ''P. gingivalis'' has been linked to [[rheumatoid arthritis]]. It contains the enzyme peptidyl-arginine deiminase, which is involved in [[citrullination]].<ref>{{Cite journal|author=Wegner, N., Wait, R., Sroka, A., Eick, S., Nguyen, K.-A., Lundberg, K., Kinloch, A., Culshaw, S., Potempa, J. and Venables, P. J. |title=Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: Implications for autoimmunity in rheumatoid arthritis |journal=[[Arthritis Rheum.]] |volume=62 |pages=2662–2672 |date=September 2010 |doi=10.1002/art.27552|issue=9}}</ref> Patients with rheumatoid arthritis have an increased incidence of periodontal disease{{Citation needed|date=October 2010}} and antibodies against the bacterium are significantly more common in these patients.<ref>{{cite journal |author=Ogrendik M, Kokino S, Ozdemir F, Bird PS, Hamlet S |title=Serum Antibodies to Oral Anaerobic Bacteria in Patients With Rheumatoid Arthritis |journal=MedGenMed |volume=7 |issue=2 |pages=2 |year=2005 |pmid=16369381 |pmc=1681585 |url=http://www.medscape.com/viewarticle/505458}}</ref>


{{reflist|2}}
''P. gingivalis'' is divided into K-[[serotype]]s based upon [[bacterial capsule|capsular]] [[antigenicity]] of the various types.<ref>American Academy of Periodontology 2010 In-Service Exam, question A-85</ref>


{{WH}}
== Virulence factors ==
{{WS}}
 
=== Gingipain===
Arg-gingipain (Rgp) and lys-gingipain (Kgp) are secreted by ''P. gingivalis.'' These [[gingipain]]s serve many functions for the organism, which contributes to its survival and virulence.<ref>{{cite journal|last=Sheets|first=S|author2=Robles-Price, A. |author3=Mckenzie, R. |title=Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis|journal=Front Biosci.|year=2012|volume=13|pages=3215–3238|pmid=18508429|pmc=3403687|doi=10.2741/2922}}</ref>
 
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 albumin serum.<ref name=Grenier>{{cite journal|last=Grenier|first=D|author2=Imbeault, S |author3=Plamondon, P. |author4=Grenier, G. |author5=Nakayama, K. |author6= Mayrand, D. |title=Role of gingipains in growth of Porphyromonas gingivalis in the presence of human serum albumin|journal=Infect Immun|year=2001|volume=69|issue=8|pages=5166–5172|doi=10.1128/IAI.69.8.5166-5172.2001|pmid=11447200|pmc=98614}}</ref> ''P. gingivalis'' can also degrade [[transferrin]] within host cells which provides the organism with an abundant iron source needed to perform multiple cellular functions.<ref name=Furuta>{{cite journal|last=Furuta|first=N|author2=Takeuchi, H. |author3=Amano, A |title=Entry of Porphyromonas gingivalis outer membrane vesicles into epithelial cells causes cellular functional impairment|journal=Infect Immun|year=2009|volume=77|pages=4761–70|doi=10.1128/IAI.00841-09|pmid=19737899|issue=11|pmc=2772519}}</ref>
 
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.<ref name=Furuta /> 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.<ref>Meuric V, Martin B, Guyodo H, Rouillon A, Tamanai-Shacoori Z, Barloy-Hubler F, Bonnaure-Mallet M (2013). "''Treponema denticola'' improves adhesive capacities of ''Porphyromonas gingivalis''". ''Mol Oral Microbiol'' '''28''' (1): 40-53.</ref> They are also associated with coordinating the integrity of the biofilm in the developing and maturation phase.<ref name=Kubinowa>{{cite journal|last=Kubinowa|first=M|author2=Hasagawa, Y. |author3=Mao, S |title=P. gingivalis accelerates gingivial epithelial cell progression through the cell cycle|journal=Microbes Infect|year=2008|volume=10|issue=2|pages=122–128|doi=10.1016/j.micinf.2007.10.011|pmid=18280195|pmc=2311419}}</ref> Lys- gingipains (Kgp) can bind to immobilized matrix proteins [[fibrinogen]] and [[fibronectin]] and may have a role in host colonization.<ref name=McAlister>{{cite journal|last=McAlister|first=A.D.|coauthors=Sroka, A; Fitzpatrick, R. E; Quinsey, N.S, Travis, J.; Potempa, J; Pike, R.N|title=Gingipain enzymes from Porphyromonas gingivalis preferentially bind immobilized extracellular proteins: a mechanism favouring colonization?|journal=J. Periodontal Res|year=2009|volume=44|issue=3|pages=348–53|doi=10.1111/j.1600-0765.2008.01128.x|pmid=18973544|pmc=2718433}}</ref>
 
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]] <ref name=Vincents>{{cite journal|last=Vincents|first=Bjarne|coauthors=Guentsch, A; Kostolowska, D; von Pawel-Rammingen, U; Eick, S; Potempa, J; Abrahamson, M|title=Cleavage of IgG1 and IgG3 by gingipain K from Porphyromonas gingivalis may compromise host defense in progressive periodontitis|journal=FASEB|date=October 2011|volume=25|issue=10|pages=3741–3750|doi=10.1096/fj.11-187799}}</ref> as well as pro[[Cytokines|inflammatory cytokines]] such as IL-1β, IL-2, IL-6, TNF-α and IL-8 in regions of high ''P. gingivalis'' concentration.,<ref name=Tanabe>{{cite journal|last=Grenier|first=D|author2=Tanabe, S|title=Porphyromonas gingivalis Gingipains Trigger a Proinflammatory Response in Human Monocyte-derived Macrophages Through the p38alpha Mitogen-activated Protein Kinase Signal Transduction Pathway|journal=Toxins (Basel)|year=2010|volume=2|issue=3|pages=341–52|doi=10.3390/toxins2030341}}</ref> which impairs 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.<ref name=Khalaf>{{cite journal|last=Khalaf|first=Hazem|coauthors=Bengtsson, T|title=Altered T-Cell Responses by the Periodontal Pathogen Porphyromonas gingivalis|journal=PLoS One|year=2012|volume=7|issue=9|bibcode=2012PLoSO...745192K|last2=Bengtsson|pages=45192|doi=10.1371/journal.pone.0045192|editor1-last=Das|editor1-first=Gobardhan}}</ref>
 
Gingipains are key factors in tissue damage symptoms of [[periodontitis]], which results from the degradation of [[Metalloproteins|matrix metalloproteins]], [[collagen]], and [[fibronectin]].<ref name=Furuta /> Degradation of these substrates interferes with interactions between host cells and the [[extracellular matrix]], therefore impeding wound healing and causing destruction of periodontal tissues.<ref name=Furuta /> 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.<ref name=Grenier />
 
=== Capsular polysaccharide ===
 
The encapsulated strain of ''P. gingivalis'' is much more virulent than the nonencapsulated strain in a mouse abscess model.<ref name=Singh>{{cite journal|last=Singh|first=A|author2=Wyant, T |author3=et al |title=The capsule of Porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagocytosis, and increase in virulence|journal=Infect Immun|year=2011|volume=79|issue=11|pages=4533–4542|doi=10.1128/IAI.05016-11|pmid=21911459|pmc=3257911}}</ref> 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.<ref name=Tanabe /><ref name=Singh /> However, other studies have found the CPS to elicit host immune responses like [[Polymorphonuclear neutrophil|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]].<ref name=D'Empaire>{{cite journal|last=D'Empaire|first=G|author2=Baer, M.T |author3=et al |title=The K1 serotype capsular polysaccharide of Porphyromonas gingivalis elicits chemokine production from murine macrophages that facilitates cell migration|journal=Infect Immun|year=2006|volume=74|issue=11|doi=10.1128/IAI.00519-06|pages=6236–43|pmid=16940143|pmc=1695525}}</ref>
 
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.<ref>{{cite journal|last=Gonzalez|first=D|author2=Tzianabos, A.O. |author3=et al |title=Immunization with Porphyromonas gingivalis Capsular Polysaccharide Prevents P. gingivalis-Elicited Oral Bone Loss in a Murine Model|journal=Infection and Immunity|year=2003|volume=71|issue=4|pages=2283–2287|doi=10.1128/IAI.71.4.2283-2287.2003|pmid=12654858|pmc=152101}}</ref>
 
=== Fimbriae ===
[[Fimbria (bacteriology)|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.<ref name=Furuta /> They were found to bind to cellular α5β1 [[integrins]], which mediated adherence and impaired the homeostatic controls of host cells.<ref name=Tsuda>{{cite journal|last=Tsuda|first=K|author2=Amano, A |author3=et al |title=Molecular dissection of internalization of Porphyromonas gingivalis by cells using fluorescent beads coated with bacterial membrane vesicle|journal=Cell Struct Funct.|year=2005|volume=30|issue=2|pages=81–91|doi=10.1247/csf.30.81|pmid=16428861}}</ref> 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''.<ref name=Hajishengallis>{{cite journal|last=Hajishengallis|first=G|author2=Wang, M. |author3=et al |title=Porphyromonas gingivalis fimbriae proactively modulate beta2 integrin adhesive activity and promote binding to and internalization by macrophages|journal=Infect. Immun. |year=2006|volume=74|issue=10|pages=5658–5666|doi=10.1128/IAI.00784-06|pmid=16988241|pmc=1594907}}</ref> ''P. gingivalis'' has long fimbriae, short fimbriae, and accessory components, each of which have distinct functions.<ref name=Kubinowa />
 
==== Long fimbriae ====
Long fimbriae (FimA), also known as major fimbriae, are long, peritrichous, filamentous components.<ref name=Lin>{{cite journal|last=Lin|first=X|author2=Wu, J. |author3=et al |title=Porphyromonas gingivalis minor fimbriae are required for cell-cell interactions|journal=Infect Immun|year=2006|volume=74|issue=10|pages=6011–6015|doi=10.1128/IAI.00797-06|pmid=16988281|pmc=1594877}}</ref> 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.<ref name=Kubinowa />
 
==== 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.<ref name=Lin /> 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.<ref name=Park>{{cite journal|last=Park|first=Y|author2=Simionato, M et al|title=Short fimbriae of Porphyromonas gingivalis and their role in coadhesion with Streptococcus gordonii|journal=Infect Immun|year=2005|volume=73|issue=7|doi=10.1128/IAI.73.7.3983-3989.2005|pages=3983–9|pmid=15972485|pmc=1168573}}</ref> This interaction may be essential in the invasion of dentinal tubules by ''P. gingivalis''.<ref name=Love>{{cite journal|last=Love|first=R|author2=McMillan, M. et al|title=Coinvasion of Dentinal Tubules byPorphyromonas gingivalis and Streptococcus gordonii Depends upon Binding Specificity of Streptococcal Antigen I/II Adhesin|journal=Infect. Immun.|year=2000|volume=68|issue=3|doi=10.1128/IAI.68.3.1359-1365.2000|pages=1359–65|pmid=10678948|pmc=97289}}</ref>
 
==== 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.<ref name=Pierce>{{cite journal|last=Pierce|first=D.L|author2=Nishiyama, S. et al|title=Host adhesive activities and virulence of novel fimbrial proteins of Porphyromonas gingivalis|journal=Infect. Immun.|year=2009|volume=77|issue=8|doi=10.1128/IAI.00262-09|pages=3294–301|pmid=19506009|pmc=2715668}}</ref>
 
=== 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.<ref name=Vincents /><ref name=Liang>{{cite journal|last=Hajishengallis|first=G|author2=Liang, S. et al|title=A Low-Abundance Biofilm Species Orchestrats Inflammatory Periodontal Disease through the Commensal Microbiota and the Complement Pathway|journal=Cell Host Microbe|year=2011|volume=10|issue=5|pages=497–506|doi=10.1016/j.chom.2011.10.006|pmid=22036469|pmc=3221781}}</ref>
 
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 [[Interleukin 8|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.<ref name=Liang />''P. gingivalis'' is able to evade opsonophagocytosis from [[Granulocyte|PMN]]’s by using Gingipain K (Kgp) to cleave [[IgG]] 1 and 3. This further modulates immune response by impairing signaling.<ref name= Vincents /> Other studies have found that ''P. gingivalis'' can subvert the [[Complement system|complement]] pathway through C5αR and C3αR, which modulates the killing capacity of leukocytes, allowing for uncontrolled bacterial growth.<ref name=Liang /><ref name=WangLiang>{{cite journal|last=Wang|first=M|author2=Liang S. et al|title=Differential virulence and innate immune interactions of Type I and II fimbrial genotypes of Porphyromonas gingivalis|journal=Microbiol. Immunol|year=2009|volume=24|issue=6}}</ref><ref name=LiangKrauss>{{cite journal|last=Liang|first=S|author2=Krauss, J.L. et al|title=The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss|journal=J. Immunol.|year=2011|volume=186|issue=2|doi=10.4049/jimmunol.1003252|pages=869–77|pmid=21149611|pmc=3075594}}</ref> ''P. gingivalis'' was also found to inhibit pro inflammatory and antimicrobial responses in human monocytes and mouse macrophages by fimbrial binding to CXCR4, inducing [[Protein kinase A|PKA]] signaling and inhibiting [[TLR-2]]-mediated immune response.<ref name=HajiWang>{{cite journal|last=Hajishengallis|first=G|author2=Wang, M. et al|title=Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function|journal=Proc Natl Acad Sci U S A|year=2008|volume=105|issue=36|doi=10.1073/pnas.0803852105|pages=13532–7|pmid=18765807|pmc=2533224|bibcode = 2008PNAS..10513532H }}</ref>
 
Once in the host cells, ''P. gingivalis'' is capable of inhibiting [[apoptosis]] by modulating the [[Janus kinase|JAK/Stat]] pathway that controls mitochondrial apoptotic pathways.<ref name=Mao>{{cite journal|last=Mao|first=S|author2=Park, Y. et al|title=Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis|journal=Cell Microbiol|year=2007|volume=9|issue=8|doi=10.1111/j.1462-5822.2007.00931.x|pages=1997–2007|pmid=17419719|pmc=2886729}}</ref><ref name=Yoshiaki /> A proliferative phenotype maybe 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.<ref name=Yoshiaki>{{cite journal|last=Kubinowa|first=M|author2=Yoshiaki, H. et al|title=P. gingivalis accelerates gingivial epithelial cell progression through the cell cycle|journal=Microbes Infection|year=2008|volume=10|issue=2}}</ref>
 
=== Community activist ===
''P. gingivalis'' is a “red” bacterium and a “keystone” bacterium in the onset of chronic adult periodontitis.<ref name=Hreview>{{cite journal|last=Hajishengallis|first=G|title=Porphyromonas gingivalis-host interactions: open war or intelligent guerilla tactics?|journal=Microbes Infect.|year=2009|volume=11|issue=6–7|pages=637–645|doi=10.1016/j.micinf.2009.03.009|pmid=19348960|pmc=2704251}}</ref> 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.<ref name=Darveau>{{cite journal|last=Darveau|first=R.P.|author2=Hajishengallis, G. et al|title=Porphyromonas gingivalis as a potential community activist for disease|journal=J. Dent. Res.|year=2012|volume=91|issue=9|pages=816–820|doi=10.1177/0022034512453589|pmid=22772362|pmc=3420389}}</ref> 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.<ref>Guyodo H, Meuric V, Le Pottier L, Martin B, Faili A, Pers JO, Bonnaure-Mallet M (2012). "Colocalization of ''Porphyromonas gingivalis'' with CD4+ T cells in periodontal disease". ''FEMS Immunol Med Microbiol'' '''64''' (2): 175-183.</ref> However, the infection mechanism of T cells by ''P. gingivalis'' remains unknown.
 
''P. gingivalis'' has been associated with increasing the virulence of other commensal bacterium 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]]''.<ref name=Inagaki>{{cite journal|last=Inagaki|first=S|author2=Onishi, S. et al|title=Porphyromonas gingivalis vesicles enhance attachment, and the leucine-rich repeat BspA protein is required for invasion of epithelial cells by "Tannerella forsythia"|journal=Infect. Immun.|year=2006|volume=74|issue=9|doi=10.1128/IAI.00062-06|pages=5023–8|pmid=16926393|pmc=1594857}}</ref> ''P. gingivalis'' short fimbriae were found to be necessary for coculture biofilm formation with ''[[Streptococcus gordonii]]'' <ref name=Park /> Interproximal and horizontal alveolar bone loss in mouse models are seen in coinfections involving ''P. gingivalis'' and ''[[Treponema denticola]]''.<ref name=Verma>{{cite journal|last=Verma|first=R.K.|author2=Rajapakse, S. et al|title=Porphyromonas gingivalis and Treponema denticola Mixed Microbial Infection in a Rat Model of Periodontal Disease|journal=Interdiscip. Perspect. Infect. Dis.|year=2010}}</ref> The role of ''P. gingivalis'' as a community activist in periodontitis is seen in 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 causes no bone loss, indicating ''P. gingivalis'' alone cannot induce periodontitis <ref name=Liang />
 
== References ==
{{Reflist|2}}


{{bacteria-stub}}
{{Periodontology}}
{{Periodontology}}

Latest revision as of 13:19, 10 April 2015

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

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Porphyromonas gingivalis belongs to the phylum Bacteroidetes 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 certain forms of periodontal disease,[1] as well as the upper gastrointestinal tract, respiratory tract, and in the colon. 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 them in the presence of considerable concentrations of antibiotics.[2] P. gingivalis also invades gingival epithelial cells in high numbers, in which cases both bacteria and epithelial cells survive for extended periods of time. High levels of specific antibodies can be detected in patients harboring P. gingivalis.

In addition, P. gingivalis has been linked to rheumatoid arthritis. It contains the enzyme peptidyl-arginine deiminase, which is involved in citrullination.[3] Patients with rheumatoid arthritis have an increased incidence of periodontal disease[citation needed] and antibodies against the bacterium are significantly more common in these patients.[4]

P. gingivalis is divided into K-serotypes based upon capsular antigenicity of the various types.[5]

Virulence factors

Gingipain

Arg-gingipain (Rgp) and lys-gingipain (Kgp) are secreted by P. gingivalis. These gingipains serve many functions for the organism, which contributes to its survival and virulence.[6]

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 albumin serum.[7] P. gingivalis can also degrade transferrin within host cells which provides the organism with an abundant iron source needed to perform multiple cellular functions.[8]

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.[8] 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.[9] They are also associated with coordinating the integrity of the biofilm in the developing and maturation phase.[10] Lys- gingipains (Kgp) can bind to immobilized matrix proteins fibrinogen and fibronectin and may have a role in host colonization.[11]

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 [12] 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.,[13] which impairs 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.[14]

Gingipains are key factors in tissue damage symptoms of periodontitis, which results from the degradation of matrix metalloproteins, collagen, and fibronectin.[8] Degradation of these substrates interferes with interactions between host cells and the extracellular matrix, therefore impeding wound healing and causing destruction of periodontal tissues.[8] 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.[7]

Capsular polysaccharide

The encapsulated strain of P. gingivalis is much more virulent than the nonencapsulated strain in a mouse abscess model.[15] 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.[13][15] 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.[16]

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.[17]

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.[8] They were found to bind to cellular α5β1 integrins, which mediated adherence and impaired the homeostatic controls of host cells.[18] 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.[19] P. gingivalis has long fimbriae, short fimbriae, and accessory components, each of which have distinct functions.[10]

Long fimbriae

Long fimbriae (FimA), also known as major fimbriae, are long, peritrichous, filamentous components.[20] 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.[10]

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.[20] 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.[21] This interaction may be essential in the invasion of dentinal tubules by P. gingivalis.[22]

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.[23]

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.[12][24]

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.[24]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.[12] 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.[24][25][26] 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.[27]

Once in the host cells, P. gingivalis is capable of inhibiting apoptosis by modulating the JAK/Stat pathway that controls mitochondrial apoptotic pathways.[28][29] A proliferative phenotype maybe 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.[29]

Community activist

P. gingivalis is a “red” bacterium and a “keystone” bacterium in the onset of chronic adult periodontitis.[30] 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.[31] 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.[32] However, the infection mechanism of T cells by P. gingivalis remains unknown.

P. gingivalis has been associated with increasing the virulence of other commensal bacterium 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.[33] P. gingivalis short fimbriae were found to be necessary for coculture biofilm formation with Streptococcus gordonii [21] Interproximal and horizontal alveolar bone loss in mouse models are seen in coinfections involving P. gingivalis and Treponema denticola.[34] The role of P. gingivalis as a community activist in periodontitis is seen in 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 causes no bone loss, indicating P. gingivalis alone cannot induce periodontitis [24]

References

  1. ↑ Naito M, Hirakawa H, Yamashita A; 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 Res. 15 (4): 215–25. doi:10.1093/dnares/dsn013. PMC 2575886. PMID 18524787.
  2. ↑ http://www.ncbi.nlm.nih.gov/pubmed/22949096
  3. ↑ Wegner, N., Wait, R., Sroka, A., Eick, S., Nguyen, K.-A., Lundberg, K., Kinloch, A., Culshaw, S., Potempa, J. and Venables, P. J. (September 2010). "Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: Implications for autoimmunity in rheumatoid arthritis". Arthritis Rheum. 62 (9): 2662–2672. doi:10.1002/art.27552.
  4. ↑ Ogrendik M, Kokino S, Ozdemir F, Bird PS, Hamlet S (2005). "Serum Antibodies to Oral Anaerobic Bacteria in Patients With Rheumatoid Arthritis". MedGenMed. 7 (2): 2. PMC 1681585. PMID 16369381.
  5. ↑ American Academy of Periodontology 2010 In-Service Exam, question A-85
  6. ↑ Sheets, S; Robles-Price, A.; Mckenzie, R. (2012). "Gingipain-dependent interactions with the host are important for survival of Porphyromonas gingivalis". Front Biosci. 13: 3215–3238. doi:10.2741/2922. PMC 3403687. PMID 18508429.
  7. ↑ 7.0 7.1 Grenier, D; Imbeault, S; Plamondon, P.; Grenier, G.; Nakayama, K.; Mayrand, D. (2001). "Role of gingipains in growth of Porphyromonas gingivalis in the presence of human serum albumin". Infect Immun. 69 (8): 5166–5172. doi:10.1128/IAI.69.8.5166-5172.2001. PMC 98614. PMID 11447200.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Furuta, N; Takeuchi, H.; Amano, A (2009). "Entry of Porphyromonas gingivalis outer membrane vesicles into epithelial cells causes cellular functional impairment". Infect Immun. 77 (11): 4761–70. doi:10.1128/IAI.00841-09. PMC 2772519. PMID 19737899.
  9. ↑ Meuric V, Martin B, Guyodo H, Rouillon A, Tamanai-Shacoori Z, Barloy-Hubler F, Bonnaure-Mallet M (2013). "Treponema denticola improves adhesive capacities of Porphyromonas gingivalis". Mol Oral Microbiol 28 (1): 40-53.
  10. ↑ 10.0 10.1 10.2 Kubinowa, M; Hasagawa, Y.; Mao, S (2008). "P. gingivalis accelerates gingivial epithelial cell progression through the cell cycle". Microbes Infect. 10 (2): 122–128. doi:10.1016/j.micinf.2007.10.011. PMC 2311419. PMID 18280195.
  11. ↑ McAlister, A.D. (2009). "Gingipain enzymes from Porphyromonas gingivalis preferentially bind immobilized extracellular proteins: a mechanism favouring colonization?". J. Periodontal Res. 44 (3): 348–53. doi:10.1111/j.1600-0765.2008.01128.x. PMC 2718433. PMID 18973544. Unknown parameter |coauthors= ignored (help)
  12. ↑ 12.0 12.1 12.2 Vincents, Bjarne (October 2011). "Cleavage of IgG1 and IgG3 by gingipain K from Porphyromonas gingivalis may compromise host defense in progressive periodontitis". FASEB. 25 (10): 3741–3750. doi:10.1096/fj.11-187799. Unknown parameter |coauthors= ignored (help)
  13. ↑ 13.0 13.1 Grenier, D; Tanabe, S (2010). "Porphyromonas gingivalis Gingipains Trigger a Proinflammatory Response in Human Monocyte-derived Macrophages Through the p38alpha Mitogen-activated Protein Kinase Signal Transduction Pathway". Toxins (Basel). 2 (3): 341–52. doi:10.3390/toxins2030341.
  14. ↑ Khalaf, Hazem; Bengtsson (2012). Das, Gobardhan, ed. "Altered T-Cell Responses by the Periodontal Pathogen Porphyromonas gingivalis". PLoS One. 7 (9): 45192. Bibcode:2012PLoSO...745192K. doi:10.1371/journal.pone.0045192. Unknown parameter |coauthors= ignored (help)
  15. ↑ 15.0 15.1 Singh, A; Wyant, T; et al. (2011). "The capsule of Porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagocytosis, and increase in virulence". Infect Immun. 79 (11): 4533–4542. doi:10.1128/IAI.05016-11. PMC 3257911. PMID 21911459.
  16. ↑ D'Empaire, G; Baer, M.T; et al. (2006). "The K1 serotype capsular polysaccharide of Porphyromonas gingivalis elicits chemokine production from murine macrophages that facilitates cell migration". Infect Immun. 74 (11): 6236–43. doi:10.1128/IAI.00519-06. PMC 1695525. PMID 16940143.
  17. ↑ Gonzalez, D; Tzianabos, A.O.; et al. (2003). "Immunization with Porphyromonas gingivalis Capsular Polysaccharide Prevents P. gingivalis-Elicited Oral Bone Loss in a Murine Model". Infection and Immunity. 71 (4): 2283–2287. doi:10.1128/IAI.71.4.2283-2287.2003. PMC 152101. PMID 12654858.
  18. ↑ Tsuda, K; Amano, A; et al. (2005). "Molecular dissection of internalization of Porphyromonas gingivalis by cells using fluorescent beads coated with bacterial membrane vesicle". Cell Struct Funct. 30 (2): 81–91. doi:10.1247/csf.30.81. PMID 16428861.
  19. ↑ Hajishengallis, G; Wang, M.; et al. (2006). "Porphyromonas gingivalis fimbriae proactively modulate beta2 integrin adhesive activity and promote binding to and internalization by macrophages". Infect. Immun. 74 (10): 5658–5666. doi:10.1128/IAI.00784-06. PMC 1594907. PMID 16988241.
  20. ↑ 20.0 20.1 Lin, X; Wu, J.; et al. (2006). "Porphyromonas gingivalis minor fimbriae are required for cell-cell interactions". Infect Immun. 74 (10): 6011–6015. doi:10.1128/IAI.00797-06. PMC 1594877. PMID 16988281.
  21. ↑ 21.0 21.1 Park, Y; Simionato, M; et al. (2005). "Short fimbriae of Porphyromonas gingivalis and their role in coadhesion with Streptococcus gordonii". Infect Immun. 73 (7): 3983–9. doi:10.1128/IAI.73.7.3983-3989.2005. PMC 1168573. PMID 15972485.
  22. ↑ Love, R; McMillan, M.; et al. (2000). "Coinvasion of Dentinal Tubules byPorphyromonas gingivalis and Streptococcus gordonii Depends upon Binding Specificity of Streptococcal Antigen I/II Adhesin". Infect. Immun. 68 (3): 1359–65. doi:10.1128/IAI.68.3.1359-1365.2000. PMC 97289. PMID 10678948.
  23. ↑ Pierce, D.L; Nishiyama, S.; et al. (2009). "Host adhesive activities and virulence of novel fimbrial proteins of Porphyromonas gingivalis". Infect. Immun. 77 (8): 3294–301. doi:10.1128/IAI.00262-09. PMC 2715668. PMID 19506009.
  24. ↑ 24.0 24.1 24.2 24.3 Hajishengallis, G; Liang, S.; et al. (2011). "A Low-Abundance Biofilm Species Orchestrats Inflammatory Periodontal Disease through the Commensal Microbiota and the Complement Pathway". Cell Host Microbe. 10 (5): 497–506. doi:10.1016/j.chom.2011.10.006. PMC 3221781. PMID 22036469.
  25. ↑ Wang, M; Liang S.; et al. (2009). "Differential virulence and innate immune interactions of Type I and II fimbrial genotypes of Porphyromonas gingivalis". Microbiol. Immunol. 24 (6).
  26. ↑ Liang, S; Krauss, J.L.; et al. (2011). "The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss". J. Immunol. 186 (2): 869–77. doi:10.4049/jimmunol.1003252. PMC 3075594. PMID 21149611.
  27. ↑ Hajishengallis, G; Wang, M.; et al. (2008). "Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function". Proc Natl Acad Sci U S A. 105 (36): 13532–7. Bibcode:2008PNAS..10513532H. doi:10.1073/pnas.0803852105. PMC 2533224. PMID 18765807.
  28. ↑ Mao, S; Park, Y.; et al. (2007). "Intrinsic apoptotic pathways of gingival epithelial cells modulated by Porphyromonas gingivalis". Cell Microbiol. 9 (8): 1997–2007. doi:10.1111/j.1462-5822.2007.00931.x. PMC 2886729. PMID 17419719.
  29. ↑ 29.0 29.1 Kubinowa, M; Yoshiaki, H.; et al. (2008). "P. gingivalis accelerates gingivial epithelial cell progression through the cell cycle". Microbes Infection. 10 (2).
  30. ↑ Hajishengallis, G (2009). "Porphyromonas gingivalis-host interactions: open war or intelligent guerilla tactics?". Microbes Infect. 11 (6–7): 637–645. doi:10.1016/j.micinf.2009.03.009. PMC 2704251. PMID 19348960.
  31. ↑ Darveau, R.P.; Hajishengallis, G.; et al. (2012). "Porphyromonas gingivalis as a potential community activist for disease". J. Dent. Res. 91 (9): 816–820. doi:10.1177/0022034512453589. PMC 3420389. PMID 22772362.
  32. ↑ Guyodo H, Meuric V, Le Pottier L, Martin B, Faili A, Pers JO, Bonnaure-Mallet M (2012). "Colocalization of Porphyromonas gingivalis with CD4+ T cells in periodontal disease". FEMS Immunol Med Microbiol 64 (2): 175-183.
  33. ↑ Inagaki, S; Onishi, S.; et al. (2006). "Porphyromonas gingivalis vesicles enhance attachment, and the leucine-rich repeat BspA protein is required for invasion of epithelial cells by "Tannerella forsythia"". Infect. Immun. 74 (9): 5023–8. doi:10.1128/IAI.00062-06. PMC 1594857. PMID 16926393.
  34. ↑ Verma, R.K.; Rajapakse, S.; et al. (2010). "Porphyromonas gingivalis and Treponema denticola Mixed Microbial Infection in a Rat Model of Periodontal Disease". Interdiscip. Perspect. Infect. Dis.

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