I|gure S ulfferlng envlronmenLal condlLlons LhaL may be encounLered by bacLerla ln Lhe varlous oral

nlches (1) upon enLry lnLo Lhe mouLh bacLerla are suspended ln sallva and experlence lower pP
osmolarlLy and LemperaLure Lhan lnLernal body levels Sallva also conLalns anLlmlcroblal facLors
lncludlng anLlbodles along wlLh proLelns and glycoproLelns LhaL can be meLabollzed by bacLerla LhaL
express Lhe necessary enzymes (2) Cnce aLLached Lo Lhe sallvary pelllcle coaLlng Lhe supraglnglval LooLh
surface bacLerla accumulaLed ln a densely packed mulLlspecles blofllm conLalnlng Lhe meLabollc
producLs and slgnallng molecules of Lhese organlsms and hosL dleLary componenLs 1emperaLure varles
beLween exLremes for example when one drlnks hoL coffee or eaLs lce cream (3) 8acLerla LhaL colonlze
Lhe glnglval crevlce are baLhed ln crevlcular fluld LhaL ls a serum exudaLe PosL polymorphonuclear
leukocyLes (Mns) and oLher lmmune cells are presenL As lnflammaLory perlodonLal dlsease
progresses Lhere ls an lncrease ln LemperaLure and bleedlng lnLo Lhe perlodonLal pockeL whlch
lncreases Lhe level of among oLher Lhlngs heme conLalnlng proLelns (4) cerLaln oral bacLerla are able Lo
lnvade Lhe hosL Llssues boLh lnLercellularly and lnLracellularly WlLhln Lhe glnglval Llssue Lhere are
normal body physlologlc condlLlons and Lhe bacLerla are also challenged wlLh hosL lmmune cells and
lmmune effecLor molecules

8AC1L8lAL CCMMunlCA1lCn
8acLerla ln complex communlLles such as blofllm communlcaLe wlLh one anoLher Lhrough a varleLy of
chemlcal slgnallng molecules lnLercellular communlcaLlon blurs Lhe dlsLlncLlon beLween slngle and
mulLlcellular organlsms and allows bacLerla Lo coordlnaLe gene expresslon and Lhus Lhe behavlor of Lhe
enLlre communlLy ln Lhls way bacLerla ln blofllms such as plaque can derlve beneflLs from Lhelr physlcal
proxlmlLry LhaL would noL be avallable Lo organlsms suspended ln flowlng flulds such as sallva
Cne means by whlch bacLerlal cells communlcaLe ls Lhrough quorum senslng cell denslLydependenL
regulaLlon of gene expresslon 1hls process lnvolves Lhe producLlon and secreLlon of slgnallng molecule
called an auLolnducer (Al) upon reachlng a Lhreshold concenLraLlon Lhe Al Lrlggers a change ln gene
expresslon Cuorum senslng can conLrol a broad range of bacLerlal acLlvlLles lncludlng vlrulence
compeLence con[ugaLlon anLlbloLlc producLlon moLlllLy sporulaLlon and blofllm formaLlonLhere are
ma[or classes of quorumsenslng sysLems CramnegaLlve bacLerla use acylaLed homoserlne lacLones as
auLolnducers (Al1) whereas gramposlLlve bacLerla uLlllze ollgopepLldes (dlscussed below) 8oLh gram
negaLlve and gramposlLve can also use an auLolnducer2 (Al2) molecule Al2 ls formed chemlcally from
43dlhydroxy23penLanedlone LhaL ls generaLed by Lhe acLlon of LuxS auLolnducer synLhase on S
rlbosylhomocysLelne Al1 slgnallng has noL been deLecLed among oral gramnegaLlve bacLerla however
many oral organlsms possess Al2 slgnallng ln glnglvalls and AcLlnobaclllus acLlnomyceLemcomlLans
LuxSbased slgnallng regulaLes expresslon of lron acqulslLlon sysLems and/or vlrulence facLors such as
proLeases ln glnglvalls and leukoLoxln ln A acLomyceLemcomlLans ln S gordonll aspecLs of
carbohydraLe meLabollsm are conLrolled Lhrough Lhls paLhway 1he Al2 slgnal also LransmlLs
lnformaLlon beLween bacLerlal specles as glnglvalls genes respond Lo A acLlnomyceLemcomlLans Al
2 1he exLenL Lo whlch Al2 slgnallng Lruly represenLs quorum senslng (le ls sLrlcLly cell denslLy
dependenL) or ls parLlally a reflecLlon of Lhe meLabollc sLaLe of Lhe cell remalns Lo be deLermlned ln
elLher evenL slnce plaque bacLerla accumulaLe Lo hlgh cell denslLy ln meLabollcally synerglsLlc
communlLles (dlscussed above) Al2 slgnallng can be we expecLed Lo play a role ln plaque developmenL
A feaLure of many specles of oral sLrepLococcl ls LhaL Lhey are able Lo exchange segmenLs of geneLlc
maLerlal (unA) wlLh hlgh frequency 1hls leads Lo conslderable adapLablllLy because new populaLlons of
cells LhaL have a selecLlve advanLage may arlse relaLlvely qulckly 1he process of upLake and
lncorporaLlon by one cell of unA exLruded by anoLher ls Lermed LransformaLlon and sLrepLococcl are
able Lo undergo Lhls process Lo naLural envlronmenL only when Lhey are ln a sLaLe of compeLence
CompeLence ls generaLed Lhrough a slgnallng mechanlsm lnvolvlng an exLracellular pepLlde pheromone
deslgnaLed compeLencesLlmulaLlng pepLlde (CS) CSs are produced by a wlde range of oral
sLrepLococcl and by sLrepLococcus pneumonlae Cells ln populaLlon secreLe low levels of CS durlng
growLh and CS gradually accumulaLes ln Lhe envlronmenL Lo reach a crlLlcal Lhreshold level Cnce Lhe
bacLerla sense Lhls Lhreshold level Lhe expresslon of genes LhaL are lnvolved ln CS producLlon are
upregulaLed (so LhaL Lhe populaLlon as a whole ls sLlmulaLed) and so are genes lnvolved ln Lhe processes
of unA upLake and recomblnaLlonulfferenL specles of sLrepLococcl produce sllghLly dlfferenL
pheromone pepLldes so LhaL more closely relaLed sLralns or specles are beLLer sLlmulaLed Lhan Lhose
more dlsLanLly relaLed Crlglnally lL was LhoughL LhaL CS producLlon was unlquely lnvolved ln
compeLence developmenL Powever lL was dlscovered laLer LhaL compeLence pheromones promoLe
oLher lnLracellular change noL necessarlly llnked Lo unA upLake and recomblnaLlon Many of Lhls change
occur Lhrough lnducLlon of expresslon of an alLernaLe 8nA polymerase slgma facLorLranscrlbes new seLs
of genes 1hus CS producLlon and senslng by S muLans ln blofllm have been foud Lo be necessary for
Lhe bacLerla Lo express proLelns necessary for Lhe cells Lo LoleraLe acld sLress and adapL Lo low pP ln
mlLls group sLrepLococcl lL ls posslble LhaL CSmedlaLed lnducLlon of Lhe unArepalr enzymes lncludlng
8ecA may be parL of a general sLress or SCS response 1hese observaLlons allow LhaL compeLence
pheromones may acLually be Lhe alarm slgnals LhaL prlme whole bacLerlal communlLles Lo oncomlng
sLress condlLlons
Cral sLrepLococcl also secreLe a wlde range of pepLldes (called bacLerloclns) LhaL are lnhlblLory Lo
bacLerlal growLh Cenerally bacLerloclns are able Lo klll compeLlng organlsms by formlng pores ln Lhe
cyLoplasmlc membrane of senslLlve gramposlLlve bacLerlal cells buL do llLLle or no harm of human cells
8acLerloclns LhaL conLaln Lhe LhloeLher amlno acld lanLhlonlne are Lermed lanLlbloLlcs and Lend Lo be
synLheslzed and secreLed Lhrough a complex machlnery of proLelns encodedby a number of genes
1hese genes are clusLered on Lhe sLrepLococcal chromosome and lnclude Lhe sLrucLural gene for Lhe
bacLerlocln (lanLlbloLlc) precursor genes encodlng modlflcaLlon and LransporL proLelns genes for
lmmunlLy and sensor and regulaLory proLeln genes lmmunlLy pepLldes provlde proLecLlon for Lhe
produclng sLraln agalnsLlLs own lanLlbloLlc whlle Lhe sensor and regulaLory proLelns provlde a
mechanlsm for senslng and respondlng Lo Lhe presence of lanLlbloLlc ln Lhls way lanLlbloLlc may also acL
as slgnallng molecules beLween sLrepLococcl Whlle senslng of CS may slgnal lmpendlng general sLress
condlLlons senslng of lanLlbloLlc may slgnal lmpendlng general sLress condlLlons senslng of lanLlbloLlc
may slgnal Lhe presence of compeLlng sLrepLococcl and sLlmulaLe a defenslve response wlLhln Lhe
populaLlon SLralns of S muLans and S sallvarlus produce poLenL lanLlbloLlcs called muLacln and
sallvarlcln respecLlvely LhaL acL on oLher specles of oral sLrepLococcl 1hese lanLlbloLlcs may Lhus play
lmporLanL roles ln deLermlnlng Lhe composlLlon of oral mlcroblal communlLles
Pence bacLerla LhaL flnd Lhemselves nelghbors as a resulL of speclflc adheslon mechanlsms and
nuLrlLlonal requlremenLs also have by whlch Lhey can communlcaLe ulfferenL specles may be able Lo
effecLlvely Lalk Lo each oLher buL Lhe exLenL Lo whlch Lhls occurs ls unknown CrossLalklng beLween
slmllar organlsms clearly may help promoLe subpopulaLlons or socleLles of organlsms LhaL Lhen have a
growLh advanLage over lndlvldual cells ln addlLlon Lhe kllllng effecLs of some slgnallng molecules wlll be
llkely Lo provlde an added advanLage Lo Lhose bacLerla LhaL are reslsLanL

CCMMunlCA1lCn Wl1P PCS1 CLLLS
1he eplLhellal cells LhaL llne Lhe glnglval crevlce provlde an lmporLanL barler funcLlon and physlcally
prevenL Lhe lngrees of bacLerla lnLo Lhe hlghly vascularlzed glnglval Llssues ln addlLlon Lo Lhls
mechanlcal role Lhe eplLhellal cells are capable of senslng and respondlng Lo Lhe presence of bacLerla
and Lhere exlsLs an elaboraLe communlcaLlon neLwork beLween bacLerlal and hosL cells 1hls molecular
dlalogue conveys lnformaLlon among Lhe bacLerla eplLhellal cells and underlylng lmmune and
lnflammaLory cells ln Lhe mucosa 1he resulLs of Lhls communlcaLlon have a slgnlflcanL effecL on Lhe
overall healLh sLaLus of Lhe glnglva rocesses LhaL can be effecLed by hosLbacLerla crossLalk range
from Lhe producLlon of lmmune effecLor molecules such as cyLoklnes Lo cell llfeordeaLh declslons
Lhrough boLh necroLlc and apopLoLlc paLhways
Cne of Lhe mosL vlslble and dramaLlc ouLcomes of Lhe lnLlmaLe assoclaLlon beLween bacLerla and
eplLhellal cells ls lnLernallzaLlon of Lhe organlsms lnLo Lhe hosL cells As eplLhellal cells are noL
professlonal phagocyLes Lhe bacLerla Lhemselves provlde Lhe molecular lnsLrucLlons Lo allow membrane
lnvaglnaLlons of Lhe hosL cells LhaL accommodaLe bacLerlal cell upLake An lnLracellular locaLlon may
beneflL bacLerla by provldlng a nuLrlnlonally rlch envlronmenL LhaL ls parLlally from Lhe ravages of Lhe
lmmune sysLem 1he role of lnLracellular lnvaslon as a vlrulence facLor for enLerlc paLhogens such as
salmonella and shlgella ls well esLabllshed and ls emerglng as an lmporLanL aspecL af Lhe
paLhophyslology of oral organlsms such as glnglvalls and A acLlnomyceLemcomlLans
ln Lhe case of glnglvalls lnvaslon ls lnlLlaLed Lhrough flmbrlaemedlaLed adheslon Lo eplLhellal cell
recepLors A serles of slgnal LransducLlon evenLs Lhen occur LhaL lead lead Lo reorganlzaLlonof boLh acLln
mlcrofllamenL and mlcroLubule cyLoskeleLal componenLs faclllLaLlng subsequenL bacLerlal enLry lnLo Lhe
cyLoplasm (llg 6A) 8oLh bacLerlal and eplLhellal cells remaln vlable followlng lnLernallzaLlon lndlcaLlng
LhaL Lhls ls a longLerm sLable assoclaLlon 1he phenoLyplc resulLs of glnglvalls havlng selzed conLrol of
a varleLy of eplLhellal cell lnLracellular paLhways have lmmedlaLe relevance Lo Lhe dlsease process
8egulaLlon of maLrlx meLalloproLelnase producLlon by Lhe glnglval eplLhellal cells ls dlLerupLed followlng
conLacL wlLh Lhe organlsm and Lhls lnLerferes wlLh exLracellular maLrlx repalr and reorganlzaLlon
lnvaslon glnglvalls also has lmpllcaLlons for lnnaLe hosL lmmunlLy SecreLlon of lnLerleukln8 by
glnglval eplLhellal cells ls lnhlblLed followlng glnglvalls lnvaslon lnhlblLlon of lnLerleukln8
accumulaLlon by glnglvalls aL slLes of bacLerlal lnvaslon could have a deblllLaLlng effecL on lnnaLe hosL
defense ln Lhe perlodonLlum where bacLerlal exposure ls consLanL 1he hosL would no longer be able Lo
deLecL Lhe presence of bacLerla and dlrecL leukocyLes for Lhelr removal 1he ensulng overgrowLh of
bacLerla could Lhen conLrlbuLe Lo an eplsodlc recurrence of perlodonLal dlsease acLlvlLy
A acLlnomyceLemcomlLans lnvades eplLhellal cells by a slmllar dynamlc mulLlsLep process lnlLlal
aLLachmenL lncudes effacemenL of Lhe mlcrovlcllll and Lhe bacLerla enLer Lhrough ruffled aperLures ln
Lhe cells membrane (flg 68) lnLernal bacLerla are lnlLlally consLralned wlLhln a hosLderlved membrane
vacuole buL Lhls membrane ls soon broken down and Lhe bacLerla are released lnLo Lhe cyLoplasm
where Lhey can repllcaLe WhaL Lhen follows ls a remarkable example of bacLerlal orchesLraLlon of hosL
cell funcLlon A acLlnomyceLemcomlLans lncudes Lhe lnformaLlon of surface membrane proLruslons
Lhrough whlch Lhe organlsm can mlgraLe and enLer lnLo ad[acenL cells 1he formaLlon of Lhese
proLruslons ls consequenL Lo bacLerlal lnLeracLlon wlLh Lhe plusends of mlcroLubules and movemenL
Lhrough Lhem may depend on bacLerlal cell dlvlslon CellLocell spread resulLs ln Lo avold lmmune
responses LargeLed Lo lnfecLed cells
lnLernallzaLlon ls noL always an ouLcome of bacLerlalhosL cell crossLalk lor example Lhe oral
splrocheLe 1denLlcola does noL lnvade llve eplLhellal cells buL does lnduce depolymerlzaLlon and
rearrangemenL of acLln mlcrofllamenLs along wlLh a loss of cellcell adheslon and subsLraLum
deLachmenL (llg 6C) ln addlLlon a splrocheLal chymoLrypslnllke enzyme can degrade [uncLlonal
complexes and can be LransporLed lnLo Lhe cell where lL dlsLurbs Lhe acLln cyLoskeleLon A ma[or surface
proLeln of Lhe 1 denLlcola can also be LranslocaLed lnLo Lhe eplLhellal cell membrane where lL forms a
conducLance lon channel and depolarlzes Lhe membrane ln llghL of Lhls onslaughL on normal eplLhellal
cell physlology lL ls unsurprlslng LhaL elevaLed numbers of Lreponemes are assoclaLed wlLh perlodonLal
dlsease
Cral bacLerla and hosL cells can be seen Lo be lnvolved ln an lnLrlcaLe and orchesLraLed serles of
lnLeracLlve evenLs 8oLh seLs of cells maneuver and manlpulaLe each oLher ln order Lo obLaln a
physlologlcal advanLage 1he adapLablllLy of hosL cells Lo encroachmenL by bacLerla plays a large parL ln
deLermlnlng wheLher Lhe bacLerla wlll be consLralned or wlll evade hosL lnnaLe defenses and cause
Llssue desLrucLlon
I|gure 6 SchemaLlc (noL Lo scale) represenLaLlon of Lhe lnLeracLlons beLween oral bacLerla and glnglval
eplLhellal cells (A) glnglvalls cells blnd Lhrough adheslns such as flmbrlae Lo lnLegrlnson glnglval cells
lAk and paxllln are recrulLed and mlcroLubules and mlcrofllamenLs are rearranged Lo faclllLaLe
lnvaglnaLlon of Lhe membrane LhaL resulLs ln Lhe engulfmenL of bacLerlal cells glnglvalls cells rapldly
locaLe ln Lhe perlnuclear area where Lhey repllcaLe Calclum lons are released from lnLracellular sLore
LhaL may regulaLe calclumgaLed pores ln Lhe cyLoplasmlc membrane CLher slgnallng molecules such as
Lhe mlLogenacLlvaLed proLeln (MA) klnase famlly can be phosphorylaLed/dephosphorylsLed or
degraded Cene expresslon ln Lhe eplLhellal cells ls ulLlmaLely affecLed Ca calclum CM cyLoplasmlc
membrane lL8 lnLerleukln 8 Ml acLln mlcrofllamenLs M1 Lubulln mlcroLubules nM nuclear
membrane phosphaLe solld arrow paLhway wlLh poLenLlal lnLermedlaLe sLeps dashed arrow
release Lwoheaded arrow reverslble assoclaLlon (8) A acLlnomyceLemcomlLans cells blnd Lhrough
adheslns such as flmbrlae and ouLer membrane proLelns Lo surface recepLors on glnglval cells 1he
eplLhellal cell membrane ruffles and effaces and lnvaglnaLlons engulf Lhe bacLerla whlch Lhen become
lnLernallzed wlLhln a membrane veslcle lnvaslon can be acLlndependenL resulLlng ln a focus of acLln
mlcrofllamenLs around Lhe bacLerla 1he bacLerlal cells desLroy Lhe membrane veslcles (posslbly by
secreLlon of phopollpase C) releaslng bacLerla lnLo Lhe cyLoplasm where Lhey grow and dlvlde rapldly
8acLerla become locallzed aL membrane proLruslons Lhrough whlch Lhey enLer ad[olnlng eplLhellal cells
ln a mlcroLubuledepdendenL process Ml acLln mlcrofllamenLs M1 Lubulln mlcroLubules dashed
arrow release (C) 1 denLlcola cells do noL enLer Lhe eplLhellal cells however Lhey secreLe a
chymoLrypslnllke enzyme (open clrcles) LhaL can degrade [uncLlonal complexes (!C) and can be
LransporLed lnLo Lhe cell where lL dlsLurbs Lhe acLln cyLoskeleLon (Ml) A ma[or surface proLeln of 1
denLlcola (ovals) can be LranlocaLed lnLo Lhe eplLhellal cell membrane where lL forms a conducLance lon
channel and depolarlzes Lhe membrane 1he resulL ls a loss of cellcell adheslon and subsLraLum
deLachmenL allowlng Lhe splrocheLes Lo access Lo Lhe proLelnrlch glnglval Llssues
kL? Cln1S
uenLal plaque LhaL develops on LooLh surfaces ls a dlverse and complex mlcroblal communlLy (blofllm)
conLalnlng more Lhan 300 specles
ColonlzaLlon of bacLerla ls ordered and sequenLlal lnlLlally plaque ls rlch ln commensals such as
sLrepLococcl and acLlnomyceLes opulaLlonal shlfLs ulLlmaLely resulL ln hlgher levels of gramnegaLlve
poLenLlal perlodonLal paLhogens such as glnglvalls A acLlnomyceLemcomlLans and 1denLlcola
8acLerlal blndlng Lo hosL surfaces and Lo oLher oral bacLerla ls lmporLanL ln Lhe developmenL of plaque
LowerafflnlLy aLLachmenL occurs Lhrough physlcochemlcal forces such as van der Waals hydrophoblc
and elecLrosLaLlc PlgherafflnlLy adheslon occurs Lhrough complemenLary adheslonrecepLor
lnLeracLlons 1hese closely flLLlng molecules can be on Lhe surfaces of bacLerla ln Lhe sallvary pelllcle on
Lhe enamel surface or on Lhe surface of hosL cells Pence bacLerla can form sLable assoclaLlons wlLh
Lhemselves and wlLh Lhe oral hard and sofL Llssues 1he paLLern of expresslon of bacLerlal and hosL cell
adheslve molecules lmparLs speclflclLy of adheslon and colonlzaLlon
Complexes of bacLerla ofLen parLlclpaLe ln complemenLary meLabollc lnLeracLlons LhaL ensure opLlmal
subsLraLe uLlllzaLlon
8acLerla can also be anLagonlsLlc Lo one anoLher Lhrough compeLlLlon for nuLrlLlonal subsLraLes and
aLLachmenL slLes and by Lhe producLlon of Loxlc meLabollLes and bacLerloclns
8acLerla ln close proxlmlLy can communlcaLe wlLh one anoLher resulLlng ln modulaLlon of phenoLyplc
properLles and poLenLlally coordlnaLlon of gene expresslon LhroughouL mulLlspecles communlLles Cne
such slgnallng sysLem ls medlaLed by Al2 produced Lhrough Lhe acLlon of Lhe LuxS enzyme Cram
poslLlve bacLerla also slgnal Lhrough shorL pepLldes such as Lhe CSs and lanLlbloLlcs
CerLaln oral bacLerla such as glnglvalls and A acLlnomyceLemcomlLans can manlpulaLe hosL cell slgnal
LransducLlon paLhways and locaLe lnLracellularly wlLhln eplLhellal cells lnLernallzed bacLerla are
proLecLed from Lhe lmmune sysLem and can affecL hosL cells may serve as a reservolr of lnfecLlon CLher
organlsms such as 1 denLlcola uLlllze secreLed bacLerlal componenLs Lo lnLerfere wlLh hosL cell funcLlons
wlLhouL lnvadlng Lhe cells