Jpn. J. Infect. Dis., 53, I‑5, 2000

Invited Review
Cu汀ent Understanding of the Cause of Dental Caries

Nobuhiro Hanada*
Department of Oral Science, National Imtitute ofInfectious Diseases
7Toyama 1‑23‑1, Shinjuku‑ku, Too,0162‑8640, Japan(Received March 3, 2000)
CONTENTS:
1. 1m廿oduction

2. Cariogenic bacteria

3･ Infection route of the mutans streptococci
4. Sucrose and dental caries

5･ Development ofa vaccine
6. Conclusion

StJMMARY: Dental caries‑associated oral streptococciare called the mutans streptococci, withStTTePtOCOCCuS
mutansand Streptococcus sobrL'nus being the most prevalent caries‑associated organismsinhumanS. Strains of
the mutans streptococciare highly conserved withinnot only mothersand their children but also racial groups,

suggesting vertical transmission of this organism withinhumanpopulations. It has been found thatthe mother‑child infection route of the mutans streptococci canbe prevented by simply reducing the amount of the mutans

streptococci containedinthe mothers'saliva. Moreover, a chlorhexidine vanish reduces the salivary mutans
streptococci byanaverage of 3 logs (99.9%),and moved them below detectable levels. We should attempt toeliminate theinfection with the mutans streptococci among Japanese people by attempting to break theinfec‑

tious chain&om mothers to children.

1. Introduction

Human beings have been exposed to various kinds ofinfectious diseases since ancient times, which have threat‑

enedtheir very existence. Many attempts have been made toprevent new and recurrent infectious diseases, which may

endanger human1ives. However, it is difncult to monitor each
infectious disease. Therefore, much attention has not been

Althoughadults have decayed teeth,inmost cases it isan
iatrogenic secondary dental caries (around restorationsand

easily developsinto pulpitis), which is a sequela of pediatricdental caries during school age. Since pediatric dental caries
is closely related to the mutans streptococci infection, it isappropriate to call it a mutrs.streptococcal disease･ Althoughtheincidence ofdentalcarleS mCreaSed aRerthe Second World
War, it is a disease that has annoyed humanbeings since

paid to commonplace infectious diseases. Dental caries isancient times; in血is sense, there has been a recu汀ent Out‑perhaps one of such disePes･ Previous reports (I‑6) havebreak of the disease. Dental caries of ancient times, however,revealed that dental caries ISaninfectious disease caused bydomesticinfection withspecific streptococci. Dentalcaries‑
associated oralstreptococciare calledthe mutans streptococci,
with Streptococcus mutaMand Streptococcus sobrinus being
the most prevalent caries‑associated organismsinhumanS.

is considered to be different舟om that encountered today.

Firstly, dental caries was encountered onlyinadultsinancient

times, whereas today it is a disease predominantly foundinchildren (14). In Japan, dental caries exclusively in adults
was fわund in the people of the Jomon era (approximately

Strains of the mutans streptococci are highly conserved

10,000 B.C. tothe 5th14thcentury B.C.) (15). Secondly, dental

within not only mothers and their chil血en but also racialcaries in ancient times was localized to the cement‑enamel

groups, suggesting a vertical transmission of this organism

Junction of the tooth, whereas, dental caries today is localized
to the enamel of the crown. 0'Sullivan, et al. examined atotal of I ,974 primary molar teethfromthe skeletal remains

within humanpopulations (6‑1 I ). Clinical trials conductedinEurOpe have shownthat it is possible to preventthe mutans
streptococciinfectionfrom mother to child (12, 13). Dental
caries that has flourished in Japanafter the Second World
War is considered to be caused bythe mother‑childinfection
withthe mutans streptococci resultingindental caries of theenamel in children.

of373 childrenfrom prehistoric times to the 18th century forcaries prevalenceand site characteristics･ Their results showedthat caries in prlmary teeth was initiated more often at thecement‑enamel junctionthanatthe contact point of the crown(16).

A look at the history of dental caries reveals that the*Corresponding author: Tel: +81‑3‑5285‑1 1 I 1, Fax: +81‑3‑5285‑

1 I 72, E‑mail: nhanada@nih.gojp
ThisarticleisanlnvitedReviewbasedonalecturepresentedat

the9thSymposlumOftheNationalInstituteofInfectious
Diseases,Tokyo,21May1999.

incidence of dental caries has nuctuated &omancient times
to today･ For example, theincidenceincreased rapidly during
the Yayoi era (the 5th‑4th century B･C･ to the 3rd century

A.D.); and is considered to have been higher during this thanthe Muromachi (1392 to 1573 A.D.) Or Kamakura (11$5 to1333 A.D.) eras (14). In modem Japan,theincidence of dental
cariesinboth primaryand permanent teeth has alsoincreased

sharply after the Second World War (17).

the biofi.lm, thereby predisposlng the tooth surface to dental

In this paper, the etiology of dental caries, which has

caries. Although, there are many oral streptococci whosechanged dramatically, lS Outlined;inaddition, progressinthe

prlmary final metabolite is lactic acid, the metabolic mecha‑

development of an anticaries vaccine and other usefulnism in the mutans streptococci seems to be different frombioactive molecules are discussed.

that in other bacteria. The mutans streptococci continuously

produce lactic acid under acidic conditions, such as at pH 4,
under which conditions dental caries may be readily produced

2･ Cariogenic bacteria(24, 25). On the other hand, while noncariogenic streptococci

With the development of carlOgenic bacteriology, it has(S. sanguis, S. salivarius, and S. mitis) other thanthe mutans

been demonstrated that current dental caries is an infectious

streptococcl produce lactic acid, they stop production underdisease caused by the mutans streptococci. The mutans strep‑

acidic conditions (26). Studies of the relationship between

tococcus is a generic name fわr seven streptococcal groups

the concentration and synthesis of lactic acid revealed that asthat exist in the oral cavityand show a unique reaction withsobrinus have been detected in the oral cavities of Japanese

the concentration of lactic acidinthe envkonmentincreases, themutans streptococci continue to produce lactic acid. However,inthe case ofS. sanguis, one of the noncanogenic streptococci,

people (6,18,19). The adhesion ofS. mutans to the toothlactic acid production declines when the concentration of

sucrose･ Among these, two species, namely, S. mutans and S.

surface takes place following a series of steps: 1)initial adhe‑lactic acid in the environment increases, and the lactic acidsion, 2) aggregation of bacteria (formation of a microcolony),

di軌ses back into the bacterial cell (26).

and 3) biofilm formation due to the function of sucrose. If an

Clinically, it can be said that the fate of teeth is decided

individual infected with the mutans streptococci does notwhen the primary teeth erupt (6). If the mutans streptococci

mgest sucrose o洗en, the bacterial microcolonies of血e toothare elevated in the saliva during the tooth emptlOn, dental

surface can be easily removed. The adhesive force of thecaries of the teeth readily develops, while if nonpathogenic

mutans streptococci to the tooth surface depends on the static

bacteria (S. sanguis, S. salivarius, and S. mitis) are dominant,electrical and hydrophobic ptOPertyof the bacterial surface
and the bonding between lectlnS and hydrogen. On the other
hand, the microcolonies of those who o洗en Ingest Sucrose(A)adhere firmly to the tooth surface because sticky water‑

垣S&mNuetnatni steSi5)

insoluble glucan is synthesized from sucroseinthe presence

gtfD

of glucosyltransferase (GTF) se.cretedfrom the mutans
streptococci. The oral microcolonleS gradually develop Intoa mature biofilm through the formation of water‑insoluble

k一一

gtfC

glucanuslng dietary sucrose. The glucanpromotes adhesion

一ト

gtLBmtltant

gtfD

of the mutans streptococci to the tooth surface. In addition,

the water‑insoluble glucan serves as a barrier that prevents

gtLIC mutant

the buffering action of saliva. Acids, which are metabolic

products of bacteria, then accumulateinthe biofilm.
Several gがgenes participate in the synthesis of water一戸soluble glucan(Table)･ Inthe case of S･ mutans,three genes,
1.e., g押, gyC,and gyp, have been identified on its chromo‑

some (20‑22). It is observed that gtj8‑ or gtfC‑deficientmutants produce the microcoloniesinthe laboratory, but lackthe ability to formbiofilm to the wall of test tubes (Fig.).

gtD mutant
gtfB

gtfC

Thus, the gtjB and gtfC genes are considered to be closely

related to the formation of biofilmand pathogenicityof this

匿国The erythromycin resistance (Emr) geneorganism. In the case ofS. sobrinus, fourGTFs were purified,

匿ヨThe tetracycline resistance (Tcr) geneand these four genes, i.e., got, g昨gqand gdU, have been

identified on its chromosome (23).

(B)

The sucrose consumed by theindividual is I) converted toglucaヮoutside the bacteria by GTF or 2) taken up by thebacterla Via mediation of the scrPTS system and metabolized
to pymvic acid, which is converted to lactic acid by a groupof glycolytic enzymes. The lactic acid decreases the pH of

Table. GTFs derived舟om the mutans streptococci

spe

c

ie

s

gがgeneenzymeglucanS. mulans gijB GTF‑I water insoluble glucan
gくjC

GTF‑SIwater

solubleandinsoluble glucans

S. sobrt'nus

g昨)

GTF‑S

water

soluble

g好

GTFII

water

insoluble

glucanglucangyS GTF‑S water soluble glucaJl

gdT GTF‑S water soluble glucan

Figure･ Insertional inactivation of the gqgenes of S･ mutaw(A), Biofllm

gdU GTF‑S water soluble glucan

formation of various stralnS OfS. mutaW inthe test tubes (B).

2

dental caries is not likely to occur (6). The glycoproteinS suchthe 1980S､by researchersinNorthem Europe and publishedas mucin contained in the saliva first adhere to the toothinthe 1 990S (1 7),and atbTaCted attention丘om all overthe world.

surface when the tootherupts. The surface coating by mucins

According to them, if the number of the mutans streptococci

is called the pellicle. Since both the pellicle and bacteria

pellicle･ However, S. sanguisand S. mitis adhere to the pellicle

containedinthe saliva of mothers is reduced to half througheducation regarding oral hygiene,infection &om mothers tochildren can be effectively prevented. Their resultsindicate

withthe aid ofbivalent cations such as Ca2+. Furthermore,inthat if the mother‑child infection can be prevented by artifi‑

possess negative charges, bacteria camot adhere easily to thethe presence of Actinomyces viscosus and Actinomyces

cial measures such as bytheuse ofa vaccine, complete elimi‑

naeslundii, which have a tendency to agglutinate with oral

nation of the mutans streptococci from the oral cavities of

streptococci, healthy bacterial plaques whose dental‑Caries‑

humans may be achievedinseveral generations. Fortunately,

induction potential is loware formed･When noncar10genic

it has not been reported that the mutans streptococci can beoral bacteria, such as S. sanguisand S. mitis, with low dental‑transmitted through the birth canal; therefore, it is reasonablecaries‑induction capacities are attached to the tooth surfaces,

to assume that childrenare notinfected with the mutans strep‑

a continual decrease in血e pH can be prevented. Therefわre,tococci at the time oferuptlOn Ofthe pr皿ary teeth. Based on

dental caries is less likely to occur than when the mutans

the results of research on the mother‑child infection of thestreptococci colonize the tooth surface, as is likely with the

mutans streptococci, children areinfected with the mutans

Ingestion of sweets.When noncar10genic bacteria with low

streptococci between approximately 19 moれ血s and 3 1 months

dental‑Caries‑induction potentialareinitially attached to theof age (8). This findingindicates thatthe mother‑childinfec‑

tooth surface, subsequent the mutans streptococci coloniza‑tion of the mutans streptococci canbe prevented by measurestion of the empted teeth is prevented, since the presence oftargeted at mothers whoare weaning babies (1 3).

the noncar10genic bacteria prevent contact between the

Sandham, et al. (29) reported that a chlorhexidine vamish,car10genic streptococciand the teeth. On the other hand, incovered witheither sealant, reduced the salivary mutans strep‑

children in whom the mutans streptococci are dominant intococci by an average of3 logs (99.9%), and moved themthe saliva during the eruption of teeth, the bacteria adheres tobelow detectable levels. Treatment with a slngle prophylaxis

the pellicle of the erupted teeth and multiply on the tooth

had no effect on mutans streptococcus levels (29). In order tosurface, especially within the pits and fissures. These teeth

prevent the earlyinfection of children with the mutans strep‑
tococci, the chlorhexidine vanish method should be applied
to mothers whoare weanlng babies.

are then most likely to develop dental caries (6).

Similarresults were confmedinanimal tests. Tanzer et al.
(27,28)investigated theincidence of dental cariesinspecific‑
pathogen‑free (SPF) ratsinfected with S. salivarius S. mutans,

4. Sucrose and dental caries

and S. sobrinus. Their results indicated that this incidence

We have isolated the activities of two tandem arranged gtf

depends on the sequence of infection with the bacteria. Rats
infected withS. salivarius, or either S. muta7V Or S. sobrinus,

genes (gtjBand gtjC) coding for GTF (GTF‑I and GTF‑SI)

Or uninfected rats were transiently co‑Gaged so as to allow(21). The third gtfgene (gtjD) coding for GTF‑S has beennatural fecal transfer of organisms due to coprophagy. Initialisolated from a different locus of the chromos?mal DNA (22)･

oral colonization of rats by S. salivarius inhibited the

To determine the role of the GTF in the car10genicityofS.

ecological emergence of fecally transmitted S. mutansand S.

mutans, we devised a strategy to replace most of the gene ofsobrinus.

GTF (gtf) with a heterologous DNAfragment coding forerythromycinresistance (Emr) or tetracycline resistance (Tcr)

Therefore, when the rats were infected first with S.

salivarius (nonpathogenic oralindigenous bacteria) prior to(Fig.). Insertionalinactivation of the gqgenesindicated thatthe mutans streptococci infection, the incidence of dental

gtjB and gtfC genes coding for GTF‑Ⅰand GTFISI activities

caries was lower than that when the rats were infected first

were required for in vitro sucrose‑dependent adherence towith the mutans streptococci Prior to S. salivariusinfection.
Since no vaccine against the mutans streptococci is currently

smooth surfaces.

available, infection with the mutans streptococci cannot be

more thanother dietary sugarS? This could be due to thecompletely prevented. Under such circumstances, it isimportant to obtain data to confim the theory that by only
delaylnginfection withthe mutans streptococci would be effec‑
tiveindecreaslng theincidence of dental cariesinchildren.

substrate‑specificityof GTF secretedfromthe mutans strepto‑

Why does sucrose predisposeindividuals to dental caries
cocci, which is nmw;therefore, GTF camot utilize substances
other thansucrose as a substrate for enzyme activity. In otherwords, the water‑insoluble glucan and oral biofilmcannot be
synthesized &om substrates other thansucrose. According toanepidemiological study, 96% of 12‑year‑Old children were

3･ Infection route of the mutans streptococci

States, its route of infection from mothers to children has

infected with the mutans streptococci in an area in Africa
where theincidence of dental caries was low (30). The
incidence of dental cariesinpeople livinginthisarea may be

gradually been clarified. However, Since it was not demon‑

low because of the low consumption of sucrose.

strated whether the mother‑child infection of the mutans
streptococci could be artiflCially prevented, this problem has

Generally speaking, avoidance of sweets isthe most impor‑tant measureinpreventing dental caries. However, differences

not been seriously discussed. In general, the prevention ofinthe "dental‑caries‑induction capacities" of glucose,血ctose,

infection by a pathogen is the option of choiceamong theand sucrose, all of which are sweet, are not widelyknown.

Afterthe discovery of the mutans streptococciinthe United

measures to preventinfectious diseases. However, the mutans

Sucrose is a disaccharide composed of glucoseandfructose

streptococci, whichare widespread throughout the world,arecontaining a high‑energy bond. The energy associated withconsidered to beanindigenous bacteriumin the oral cavity

the hydrolysIS Of sucrose to glucose andfructose plays animportant role in the induction of dental caries. The free

and the prevention of infection with the mutans streptococci
is consideredunlikely. The results of clinical tests conductedinenergy produced by hydrolysis of the high‑･･energy bond in3

sucrose is 6,600 Gal‑mol. The GTF secreted from the mutans

prevention of dental caries (37).

streptococcI POlymerizes glucose, uslngthe energy obtained

Kelly et al. (38) inhibited the binding of a cell‑surface

throughthe hydrolysis of sucrose to glucose and fructose,

adhesin of S. mutans to salivary receptors uslng a Synthetic

resultinginthe synthesis of water‑insolubleglucan. Therefore,

peptide blO25) Corresponding to residues 1025‑1044 0fthe
adhesin. Two residues withinpl025that contribute to binding

if one Ingests glucose or f山ctose instead of sucrose, nohydrolysis energy lS generated, water‑insoluble glucanis notsynthesized,andthe "dental‑caries‑induction levels"are low.
Dental caries isaninfectious disease,and whether or not one

were identified by site‑directed mutagenesis. In an in vivo

will develop dental caries strongly depends ontheamount of

notActinomyces, as compared witha controlpeptide or saline･

human streptococcal adhesion model, direct application or
p1025 to the teeth prevented recolonization of S･ mutans but

sucrose consumed. Even if infection cannot be prevented,

These strategleS may be used against other pathogenic

dental caries can be ameliorated by reducing the consump‑bacteria in which adhesins mediate colonization of mucosaltion of sucrose.

surfaces.

5. Development of a vaccine

6. Conclusion

A cell‑surface adhesinofthe mutans streptococci may be
involvedinthe binding of bacteria to the tooth surface,and

infection with the mutans streptococci is possible were not

has long been focused upon as a candidate for a preventive

available until the 1990S, no Japanese public health center

Since the clinical data indicatlng that the prevention of

vaccine for dental caries. The peptide PAc (365‑377) was

consideredthe prevention ofthisinfection, which is widespreadshowntomiseanandbodyinmice, which inhibitedthe binding

throughout the world. As I have discussed in this paper, inclinical trials it has been found thatthe mother‑childinfectionof salivary components to the cell‑surface adhesin. Usingthis
peptide as a unit peptide, two constructs based on multiple
antigenic peptides, and several types of tandem repeats ofroute of the mutans streptococci can be prevented by simply

two orthree copleS Were Synthesized to estimatethe immun0‑

mothers'saliva. Moreover, a chlorhexidine vanish reduces

genicityofthesepeptides (3 1‑35).Anincreaseinthe immun0‑

the salivary mutans streptococci by an average of 3 logs

genicitywas observed for all constructs with the use of an(99.9%),and movedthem below detectable levels. We should

adjuvant compared to the unit peptide alone. However, thetandem repeat constructs generallyinducedantibody produc‑

attempt to eliminatetheinfection withthe mutans streptococci
by attempting to breaktheinfectious chain from mothers totioninthe absence ofanadjuvant, whilethe multipleantigenic

children.

reducingthe amount of the mutans streptococci containedin

peptide constructs did notinduceantibody production under
the same conditions (35). Although such a phenomenon may

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