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PLOSPathogens:Streptococcusmutans,Candidaalbicans,andtheHumanMouth:AStickySituation

Streptococcus mutans, Candida albicans, and the Human Mouth: A


Sticky Situation
KhalidH.Metwalli, ShariqA.Khan, BastiaanP.Krom, MaryAnnJabraRizk
Published:October17,2013

DOI:10.1371/journal.ppat.1003616

FeaturedinPLOSCollections

Citation:MetwalliKH,KhanSA,KromBP,JabraRizkMA(2013)Streptococcusmutans,Candidaalbicans,andtheHuman
Mouth:AStickySituation.PLoSPathog9(10):e1003616.doi:10.1371/journal.ppat.1003616
Editor:JosephHeitman,DukeUniversityMedicalCenter,UnitedStatesofAmerica
Published:October17,2013
Copyright:2013Metwallietal.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommons
AttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthor
andsourcearecredited.
Funding:ThisworkwassupportedbyNIHgrantDE016257.Thefundershadnoroleinstudydesign,datacollectionand
analysis,decisiontopublish,orpreparationofthemanuscript.
Competinginterests:Theauthorshavedeclaredthatnocompetinginterestsexist.
Introduction

Thehumanmouthwithitsdiversenichesandamplesupplyofnutrientsisundoubtedlyconducivefortheunrestrictedformationof
naturalmicrobialbiofilms.Theoralmicrobialcommunitiesaresomeofthemostcomplexmicrobialflorasinthehumanbody,
consistingofmorethan700differentbacterialspecies[1],[2].Occurrenceofdiseaseresultsfromdisturbanceoftheequilibriumof
thiscomplexecosystem,wherepopulationshiftsleadtooverrepresentationofpathogenicspecieswhichcontributetotheonset
andprogressionofthemostcommonoraldiseases,cariesandperiodontaldisease[3].Cultureindependentmolecularmethods
suchasproteomicsand16SrRNAsequencingaimingtodeterminethebacterialdiversityinthehumanoralcavityhave
demonstratedthatinthesupragingivalplaque,S.mutanswasthedominantspecies,withelevatedlevelsofotherstreptococci
includingS.sanguinis,S.mitis,andS.salivariusinadditiontolactobacilliandVeillonella.Incontrast,thesubgingivalplaquewas
madeupprimarilyofGramnegativeanaerobicbacteriasuchasFusobacteriumnucleatum,Porphyromonasgingivalis,and
Prevotellaintermediawhichareknowntobeperiodontalpathogens[3][5].
Thedentaltissuesenamel,dentin,andcementumconstitutetheoralsolidsurfacescoatedbyapellicletowhichthemicrobial
cellsattach.Theprimarycolonizersandsecondaryorganismssticktoeachotheronthesurfaceofteethandgenerateamatrixof
exopolysaccharidewithinwhichcellsgrow,formingacommunitywithacollectivephysiology[6].Theresultingbiofilmformed,
knownasdentalplaque,subjectstheteethandgingivaltissuestohighconcentrationsofmicrobialmetaboliteswhichresultin
dentaldisease[2],[7].Theinteractionsbetweenthevariousspeciesinthesemixedbiofilmscanbesynergisticinthatthepresence
ofonemicroorganismgeneratesanicheforotherpathogenicmicroorganismswhichcanservetofacilitatetheretentionof
organisms,anoralphenomenonknownascoaggregation[3],[8].Thebacteriainthebiofilmarealwaysmetabolicallyactivewhich
causesfluctuationsinpHandlossofmineralsfromthetooth,ultimatelyresultingindissolutionofthedentalhardtissuesand
formationoflesionsknownasdentalcaries[6],[9].Interestingly,metaboliccommunicationsamongoralbacteriamayoccurwhere
theexcretionofametabolitebyoneorganismisusedasanutrientbyotherorganismsandbreakdownofasubstratebyenzymatic
activityofoneorganismcreatesavailablesubstratesfordifferentorganisms[10],[11].
DentalCaries

Dentalcariesortoothdecayisamongthemostprevalenthumandiseases,secondonlytothecommoncold[12].Cariesisa
chronicdiseasethatprogressesslowlyandischaracterizedbylocalizedandirreversibledestructionofthetooth[13],[14].Despite
scientificadvancementsincariologyinthepast150years,dentalcariesremainsaseriousissueworldwide,particularlyinchildren
whereitistheprimarysourceoftoothloss.IntheUnitedStates,42%ofchildrenofagesbetween2to11havehaddentalcariesin
theirprimaryteeth,andintheadultpopulation,dentalcariesandperiodontaldiseasesaffect6090%ofindividualsworldwide[13].
Peoplewithdisabilitiesandlowersocioeconomicstatussufferfromthehighestprevalenceandpathogenicityofdentalcaries.
Cariesresultsfromthecomplexinteractionsamongthemicrobialspeciesadheringtothetoothsurface,withdietary,salivary,and
geneticinfluences.Themetabolicmicrobialinteractionsthattakeplaceinthedentalbiofilmresultinacidproductionand
extracellularglucanformationwhichpromotemicrobialattachmenttoteeth[6],[12],[13].Ninetypercentofcariouslesionsoccurin
thepitsandfissuresofpermanentposteriorteethandmolarteethasthebiofilmtendstostagnateandmatureintheseareaswhich
arerelativelyprotectedfrommechanicalwearbythetongue,cheeks,andtoothbrushing[6].Therecognitionofacidasthecentral
etiologicalagentindentalcariesinitiatedasearchforthecausativemicroorganismsintheoralmicrobiota,andintheearly1960s,
thebacterialspeciesStreptococcusmutans(S.mutans)becamethemainfocusofcariesresearch,assumedtobethespecific
cariogen[15].
Streptococcusmutans:TheUsualSuspect

StreptococcusmutansareGrampositivebacteriathatresideinthehumanmouthand,morespecifically,inthemultispecies
biofilmsonthesurfacesofteeth[14].Streptococcusmutansaremajorcariogenicorganismstheresultoftheirabilitytoproduce
largequantitiesofglucansaswellasacid,exceedingthesalivarybufferingcapacities,whichgivesthebacteriaanadvantageto
outcompetenoncariogeniccommensalspeciesatlowpHenvironments[9],[16].Thisabilitytosurviveinanacidenvironmentby
modulatingsugarmetabolicpathwayscoupledwithirreversiblebindingtoteethisakeycomponenttoS.mutanspathogenesis.In

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PLOSPathogens:Streptococcusmutans,Candidaalbicans,andtheHumanMouth:AStickySituation

thesecondstageofinvasion,S.mutanscoadhereorcoaggregatewithothermicrobialspecies,followedbyproliferationandspread
intoothersitesintheoralmucosamodulatedbyconcertedactionofgenesandsignalingmolecules.Inthefinalstage,thebiofilm
reachesasteadystatewhichchangestheequilibriumbalanceoftheoralecologyasaresult,bacteriagainaccessintothedeeper
tissuesandrecessesinthegingivalareas,ultimatelycausingdissolutionofhydroxyapatitecrystalsinenamelanddentinwhich
resultsincavitationwithinthetooth[12],[17].Ifnotprevented,thiscavitationprovidesanecologicalnichewheremicroorganisms
formaprotectedbiofilm,enablingcariestoprogressgradually[13].Interestinglyhowever,althoughithasbeenacceptedfor
decadesthatS.mutansistheetiologicagentofdentalcaries,recentevidenceindicateshighprevalenceforS.mutansindental
biofilmswherethefungalpathogenCandidaalbicans(C.albicans)resides,suggestingthattheinteractionbetweenthesediverse
speciesmaymediatecariogenicdevelopment[18],[19].
Candidaalbicans:PartnerinCrime?

Candidaalbicansisacommensalfungalspeciescommonlycolonizinghumanmucosalsurfaces[20].However,underconditionsof
immunedysfunctionsuchasHIVinfection,C.albicanscanbecomeopportunisticpathogenscausingmucosalanddisseminated
infections.TheabilityofC.albicanstoswitchitsmorphologybetweenyeastandhyphalformscontributestoitspathogenesis[20].
Intheoralcavity,thecoadhesionbetweenC.albicansandoralbacteriaiscrucialforC.albicanscolonizationandpersistence[21].
Inadditiontoprovidingadhesionsites,thestreptococciexcretelactatethatcanactasacarbonsourceforyeastgrowth,whichin
turnreducesoxygentensiontolevelspreferredbystreptococciandprovidegrowthstimulatoryfactorsforthebacteria[21].
IncreasinginterestworldwideseemstofocusontheroleofC.albicanscoaggregationwithS.mutansduringadherencetodental
surfaces[18].ThehypothesisoftheassociationbetweenS.mutansandC.albicansisbasedontheirmechanismsofvirulenceand
biochemicalcharacteristicsaswellashostfactorsthatprovideabuccalenvironmentfavoringtheactionofbothmicroorganisms
[17][19].Infact,severalinvitrostudieshaveshownthatC.albicansenhancetheadherenceofS.mutans,indicatingapossible
facilitationmechanismduringtheirassociationwheretheyeastcellscouldbeusedbythebacteriaassupportforadherence[17],
[19].Scanningelectronmicroscopicanalysisofmixedspeciesbiofilmsgrownonhumanteethandhydroxyapatiteassubstrata
confirmedthestrongcoadherencebetweenC.albicansandS.mutanstothesesurfacesandtoeachother,withS.mutans
exhibitinghighaffinitytotheC.albicanshyphae(Figures1and2).Moreimportantly,theyeast'spotentialtoinducedentalcariesas
aconsequenceofitspronouncedabilitytoproduceandtolerateacidswassupportedbyarecentstudybyKlinkeetal.[22],
providingexperimentalevidenceinvivothatC.albicansiscapableofcausingadvancedocclusalcariesinratsatahighrate.The
findingsfromtheseinvitroandanimalstudiesattributingaroleforC.albicansincariesdevelopmentand/orprogressionwere
solidifiedbydatafromaclinicalstudywheretheoccurrenceofcariesinchildrenwaspositivelycorrelatedwiththefrequencyoforal
candidalcarriage[17].Althoughstillinitsinfancy,theresearchthusfarstronglywarrantsthatinvestigationsonthemicrobiologyof
cariesshouldincludeyeasts[22].

Figure1.ScanningelectronmicrographsofmaturemixedbiofilmsofC.albicansandS.mutansgrownonextractedhumanteeth,
demonstratingthetightcoadherencebetweenC.albicanshyphae(redarrows)andS.mutanscells(bluearrows).

Microbialcellscanbeseenembeddedinamatrixofextracellularpolymericsubstancewithwaterchannels(whitearrows)
throughwhichliquidflowsdistributingnutrientsandsignalingmoleculesthatfacilitatecommunicationbetweenthecells.Bars
10m.
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PLOSPathogens:Streptococcusmutans,Candidaalbicans,andtheHumanMouth:AStickySituation

Figure2.Scanningelectronmicrographsofmaturemixedbiofilmsformedondiscsofhydroxyapatite(amajorcomponentandessential
ingredientofnormalteeth),demonstratingtheaffinityofS.mutanstothehyphalelementsofC.albicans.

Bacterialcellsareseenattachedinchainsastheyadheretoandwraparoundthehyphae.Perforationscanbeseeninthe
hydroxyapatitesurface(whitearrows),possiblytheresultofdecalcificationofthematerialduetothehighacidicenvironment.
Bars10m.
doi:10.1371/journal.ppat.1003616.g002

TherapyandChallenges

Asteethlossinbothchildrenandadultshasbecomeafinancialburdenworldwide,understandingthehomeostaticsynchrony
betweentheresidentmicroflora,therebypreventingbiofilminducedcariesandimprovingthequalityoflife,hasbecomecrucial.
Althoughregularremovalofbiofilmonthetoothandtheincorporationoffluorideintoothpastehasbeenthemainstayofdental
cariesprevention,thesepracticesofferincompleteprotectionandmaynoteffectivelyaddresstheinfectiouscharacterofthe
disease[6],[16].Unfortunately,designingeffectivetherapiestotreatcarieshasbeenamajorchallenge,particularlyintermsoforal
drugdeliverysystemsthatcanpenetratethebiofilmnetworksofthetargetlocation[12],[16].Antimicrobialpeptidessuchasthe
histatinsareconsideredpromisingagentsduetotheirbroadspectrumantimicrobialproperties[23],[24].However,several
questionsabouttheuseofthesemoleculesasatoolformicrobialcontrolremainunclear.Therecentsearchformoreeffective
antimicrobialshasexploredthepotentialuseofnanotechnologytoimprovethephysicalandchemicalpropertiesofdrugswhere
nanosystemformulationsincorporatingdifferentagentscanimprovestabilityandantimicrobialactivity[25].Otherstudies
investigatedtheuseofactiveinhibitorsofenzymesthatmakeuptheexopolysaccharidematrix,therebyaffectingthecariogenic
biofilmassembly.Datageneratedfromthesestudiesdemonstratedthatincombinationwithfluoride,thenewantibiofilm
compoundssuccessfullyinactivatedexopolysaccharideaccumulationandmatrixdevelopment[16].However,althoughpromising,
thesecompoundsareyettobejustifiedininvivostudiestofurtherevaluatetheirapplicabilitypavingthedirectiontowardclinical
applications.
ConclusionandFutureDirections

Microbialcommunityinteractionsinhealthandcariespathogenesisarenotwellunderstood.Ithasbeenproposedthatthe
translocationoforalbacteriatoremotesitescanleadtosystemicdiseasessuchascoronaryarterydisease[3].Therefore,
unravelingthebasisofdentalplaquedevelopmentwillultimatelycontributetobothoralandoverallhealth.Tothatend,using
moleculartechniques,currentstudiesarefocusingonidentifyingassociationsbetweenoralbacteriaandvariousoralandsystemic
diseases.Althoughinvitrostudiescancontributetoourunderstandingofthecomplexmicrobialassociationsandthedynamicsof
theirinteractionintheoralenvironment,theimmunocompetenceofthehostandfactorssuchasdietandoralhygieneplayan
importantregulatoryfunction.TobetterunderstandtheimpactoftheinteractionbetweenC.albicansandS.mutansoncaries
developmentinahost,itiscrucialtodeterminemechanisticallyprecisedetailsofadhesionandsignalingunderconditionsof
coexistenceandtoidentifythemolecularprocessesinvolvedinthedevelopmentofcariogenicbiofilmsinthehost.Bymanipulation
ofadhesioninteractions,itmaybepossibletodevelopnewprotocolstoblockadhesivereactions,impedingdevelopmentofbiofilm
relatedoraldiseasesuchasdentalcaries[9],[22],[26].Therefore,thepresenceofC.albicansintheoralenvironmentcannowbe
consideredanadditionalfactorthatneedstobetakenintoaccountinevaluatingriskstocaries[18].Tothatend,futurestudies
shouldfocusonclinicalstudiesandondesigninganimalmodelsystemstostudyinvivogrownpolymicrobialbiofilms,withthegoal
ofdevelopingnoveltherapeuticstrategiestopreventdentalcariesthroughtargetedactions.
Acknowledgments

WewouldliketothankDr.RuChingHsiaandtheUniversityofMarylandCoreImagingFacilityforassistancewithelectron
microscopy.ThisworkwassupportedbyNIHgrantDE016257NIH/NAIDandtheInteruniversityAttractionPolesProgramme
initiatedbytheBelgianSciencePolicyOffice.
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