Colonizacion Oral Por Candida Albicans

ORAL COLONIZATION BY CANDIDA ALBICANS
R.D. Cannonl*
W.L. Chaffin2
'Department of Oral Sciences and Orthodontics, Faculty of Dentistry, University of Otago, PO Box 647, Dunedin, New Zealand; 2Department of Microbiology and Immunology, Texas Tech
University Health Sciences Center, Lubbock, Texas, USA; *corresponding author
ABSTRACT: Candida albicans is a commensal yeast normally present in small numbers in the oral flora of a large proportion of
humans. Colonization of the oral cavity by C. albicans involves the acquisition and maintenance of a stable yeast population.
Micro-organisms are continually being removed from the oral cavity by host clearance mechanisms, and so, in order to survive
and inhabit this eco-system, C. albicans cells have to adhere and replicate. The oral cavity presents many niches for C. albicans
colonization, and the yeast is able to adhere to a plethora of ligands. These include epithelial and bacterial cell-surface molecules, extracellular matrix proteins, and dental acrylic. In addition, saliva molecules, including basic proline-rich proteins,
adsorbed to many oral surfaces promote C. albicans adherence. Several adhesins present in the C. albicans cell wall have now
been partially characterized. Adherence involves lectin, protein-protein, and hydrophobic interactions. As C. albicans cells evade
host defenses and colonize new environments by penetrating tissues, they are exposed to new adherence receptors and
respond by expressing alternative adhesins. The relatively small number of commensal Candida cells in the oral flora raises the
possibility that strategies can be devised to prevent oral colonization and infection. However, the variety of oral niches and the
complex adherence mechanisms of the yeast mean that such a goal will remain elusive until more is known about the contribution of each mechanism to colonization.
Key words. Candida albicans, colonization, adherence, candidiasis.
(1) Introduction
population studied. A compilation of data from a number of reports showed that the mean carriage rate for
healthy individuals (no known underlying disease) was
17.7% (range, 1.9-62.3%), whereas mean carriage in hospitalized individuals (without clinical candidiasis) was
40.6% (range, 6.0-69.6%) (Odds, 1988). These data indicate that the health of an individual is a predisposing
factor for C. albicans colonization. A large number of sites
in the oral cavity can be colonized; in healthy individuals,
C. albicans is most commonly isolated from the mid-line
of the middle and posterior thirds of the tongue, the
cheek, or the palatal mucosa (Arendorf and Walker, 1979,
1980; Borromeo et al., 1992).
It is of interest that only a proportion of the population is colonized by C. albicans, and only a subset of these
individuals develops candidiasis. Few longitudinal studies have been carried out on healthy individuals to see if
Candida colonization is continuous. However, daily sampling has shown that C. albicans carriage persisted in a
proportion of healthy people and that colonization
recurred in a majority of the remaining subjects (Gergely
and Uri, 1966; Williamson, 1972). In a study of 163
neonates in an intensive care and surgical unit, 21 of the
neonates initially carried C. albicans in their mouths, but
only five yielded 6 or more yeast-positive cultures over
the 17-week study period (Sharp et al., 1992). These
neonates were colonized for periods of between 7 and 63
The presence of Candida albicans in the oral cavity is not

indicative of disease. In many individuals, C. albicans is
a minor component of their oral flora, and they have no
clinical symptoms. In certain sections of the population,
however, oral candidiasis occurs frequently and necessitates antifungal therapy. Oral presentations of candidiasis vary from the large white plaques of pseudomembraneous candidiasis on the tongue and buccal mucosa to
the palatal erythematous lesions of chronic atrophic candidiasis, and to angular cheilitis on the labial commissures (Samaranayake, 1990; Scully et al., 1994; Shay et al.,
1997). The primary etiological agent of oral candidiasis is
the yeast C. albicans; however, other species that cause
disease less commonly include C. tropicalis, C. glabrata, C.
krusei, C parapsilosis, C. guilliermondii, and C. dubliniensis
(Odds, 1988; Fridkin and Jarvis, 1996; Sullivan and
Coleman, 1998). Sequelae of mucosal colonization, particularly of the gastrointestinal tract, may include penetration of the vascular system by Candida cells and
hematogenous dissemination (Cole et al., 1996). These
cells can then infect a variety of organs in immunocompromised individuals and cause disseminated or systemic disease.
It is difficult to give a precise oral carriage rate for C.
albicans, since this depends on the age and health of the
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Colonization
Acquisition
(2) Acquisition
Candida species inhabit a variety of

environments (Odds, 1988). C. albi-
(a)
cans
frommammals,
primates,
has been isolated
domesticated
and other
b)
Systemic
Disease
and birds. In contrast,

marsupials,
Candida species have been isoother
lated from a much narrower range of
hosts (Odds, 1988). In humans, C.
diseases Oral
Oa cavity
preferentially colonizes
Ialbicans
mucosal surfaces, and the intestinal
GWt C. albicans
\
\i'
Removal
(c)
(d)
Mucosl
Figure 1. A model showing the interrelationship of factors involved in colonization of the oral
cavity by C. albicans: (a) acquisition, (b) growth, (c) removal, and (d) tissue damage and
penetration.
days. The C. albicans strains were biotyped, and there was

unequivocal evidence for more than one infecting biotype in only 8.1% of colonized neonates. In immunocompromised hosts, candidiasis is often caused by a resident
strain (Powderly et al., 1993; Voss et al., 1994), and the
same strain can cause recurrent infections (Miyasaki et
al., 1992). Some of the factors involved in the balance
among clearance of C. albicans, colonization, and the
development of candidiasis have been reviewed previously (Cannon et al., 1995a). The objective of this review
is to focus on the initial, critical, step of colonization,
and to discuss the factors involved in colonization and
how current research might lead to therapeutic interventions that could prevent colonization and, thus, preclude
candidiasis.
Colonization of the oral cavity by C. albicans can be
defined as the acquisition and maintenance of a stable
population of C. albicans cells which does not give rise to
clinical disease. A model based on this definition is
shown in Fig. 1. Colonization depends on the rate of
acquisition-that is, the rate at which yeast cells enter
the oral cavity-growth, and removal of cells from the
mouth by swallowing and oral hygiene. In a simplified
model, if the rate of removal is greater than that of acquisition and growth, clearance will take place. If the rate of
removal is the same as that of acquisition and growth,
then there will be colonization. If the rate is lower and
there is tissue damage, it will lead to candidiasis. The
presentation of candidiasis will depend on the tissue
colonized, the virulence factors expressed by the Candida
cells, and the host response. So, colonization depends
on several factors: the acquisition or entry of cells into
the oral cavity, the attachment and growth of those cells,
the penetration of tissues, and the removal of cells from
the oral cavity. Each of these factors will be examined.
360
360
tract is believed to be a major reserCole et

(Odds, can
1988;colonize
voir
infection
al., for
1996).
C. albicans
practically any site in the gastrointestinal tract (Cole et al., 1996), from
the oral cavity to the rectum and

peri-anal tissues, allowing anal-oral
inoculation to occur (Soll et al., 1991).
The vulvovaginal regions of approximately 40% of
healthy women are colonized by Candida species (Soll et
al., 1991), and the genito-urinary tract presents another
reservoir for oral inoculation. C. albicans survives better
on moist surfaces than dry inanimate objects, but if the
degree of contamination is high enough, viable cells will
remain on dry surfaces for at least 24 hours (RangelFrausto et al., 1994). Many studies of nosocomial candidiasis in clinical settings have been carried out to
determine how patients acquire infections (Hunter et al.,
1990; Vazquez et al., 1993, 1998; Fridkin and Jarvis, 1996).
It is evident that the most common means of transfer is
contact with carriers, often the hands of hospital staff,
although various Candida species can be cultured from
inanimate objects (Hunter et al., 1990; Vazquez et al., 1993,
1998; Strausbaugh et al., 1994; Jarvis, 1996; Pfaller, 1996).
A worrying finding in one of these studies was that C.
albicans could be cultured from the food given to two
patients in a bone marrow transplant unit (Vazquez et al.,
1993). Indeed, yeasts, including Candida species, are relatively common contaminants of both processed and
unprocessed foods (Buck et al., 1977; Viljoen and
Greyling, 1995). In a dental setting, the internal surfaces
of dental unit water lines can become coated with bacteria-rich biofilms (Tippett et al., 1988; Peters and McGaw,
1996). Although there are no reports of yeasts being present in these biofilms, this may reflect the culturing
methods used. If C. albicans were a component of such
biofilms, contaminated water lines could constitute a
significant risk of inoculating oral cavities with yeast. In
people whose mouths are colonized with C. albicans, the
yeast can be found in saliva at an average concentration
of 300 to 500 cells per mL (Arendorf and Walker, 1980).
This will allow for transfer during kissing and other direct
saliva-saliva contact. There are ample opportunities,
ritRevOralBio Me
lO3):39 33 (999
10(3):359-383 (1999)
therefore, for the entry of Candida

species into the oral cavity by manual
inoculation, saliva transfer, or contami-
(a)
nated food and drink.
(3) Maintaining an Oral

Candida Population
The entry of Candida cells into the oral
cavity is not sufficient for colonization;
they must be stably maintained. Since (b)
the oral cavity is a continuous-flow
environment, yeast cells will be washed
out by saliva and swallowed unless
they adhere and replicate. Growth conditions in the oral cavity are so poor
(there is practically no growth in saliva
unless it is supplemented with glucose
lSamaranayake et al., 19861) that cells
have to adhere to be maintained.
Adhesion is therefore of critical importance in colonization. Adherence is
mediated between moieties of the
Candida cell wall and host surfaces, and Figure 2. Molecular interactions between the cell wall of C. albicans and oral surfaces. (a)
so an understanding of colonization Schematic representation of the architecture and composition of the C. albicans cell wall:
relies upon knowledge of these sur- 41M chitin, 41i49 3(1,3)-glucan, "`..i 13(1,6)-glucan, .L, mannoprotein, (&
phosphodiester linkage, and
faces.
plasma membrane. (b) Interactions of C. albicans with
molecules and surfaces in the oral cavity that may contribute to colonization.
(A) THE C. ALBICANS CELL WALL
The cell wall is essential both to the biology of C. albicans
polymer of N-acetylglucosamine) is a minor constituent
and to its interactions with the human host in health and
that is variously reported to contribute from 1 to 10% of
disease. Although frequently called a dimorphic fungus,
the cell wall's dry weight. The higher levels are associatthe organism is, in fact, polymorphic and may adopt
ed with hyphal cells which are reported to contain
growth not only in yeast or hyphal modes but also as
approximately three times more chitin than yeast cells.
pseudohyphae and may produce chlamydospores in cerHowever, a recent study reports that chitin measuretain growth conditions (Odds, 1988). The initial emerments depend greatly on the method used (Munro et al.,
gence of hyphae from yeast cells is often referred to as
1998). (-glucan (a branched polymer containing 3-1,3
germ tube formation. While both yeast and hyphae can
and 3-1,6 linkages) is the main constituent, accounting
be found in lesions, and different adhesins are expressed
for 47 to 60% of the cell wall's dry weight. These two
on hyphae as discussed below, hyphal cells clump extenmicrofibrillar polysaccharides, while found throughout
sively and have been less-well-studied in adherence
the cell wall, are more concentrated in the inner portion
assays than yeast. The cell wall is the structure responsinear the plasma membrane and provide a rigid skeleton.
ble for supplying the rigidity that maintains the unique
The other main component is mannan, also sometimes
shapes that characterize fungal growth. The surface of
called phosphomannoprotein or phosphopeptidomanthe organism is the site of the physical interactions
nan complex, which accounts for about 40% of the cell
between the fungus and host proteins and tissues that
wall. Mannans are composed of mannose polymers covalead to adherence, and between the fungus and the
lently linked to a protein moiety mostly by N-glycosidic
immune system that lead to clearance.
linkages through di-N-acetylchitobiose to asparagine
The cell wall is composed primarily of carbohydrate
residues. The mannose component consists of a back(80-90%), 1-glucan, chitin, and mannan (Fig. 2a; for more
bone of (x-1,6-linked mannose molecules to which are
extensive discussion, see reviews by Shepherd, 1987;
attached oligosaccharide side-chains containing manCassone, 1989; Fleet, 1991; Fukazawa and Kagaya, 1997;
nose residues with ax-1,2, ox-1,3, 3-1,2, 13-1,6 linkages and
Chaffin et al., 1998). The components of the cell walls
some a-1,6 branches. Some of these side-chains also
from yeast and hyphal forms are similar, although there
contain a phosphodiester linkage to short 1-1,2 mannois some quantitative variation. Chitin (an unbranched
oligosaccharides. The N-glycosyl moieties of high-molec359 383 (I1999)
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TABLE 1
C. albicans Adhesins and BEC Ligands
Ligand
Reference
Unknown
Unknown
Segal, 1996
Miyakawa et al., 1992
Glycosphingolipid
Yu et al., 1 994a
Fibronectin
Klotz and Smith, 1992; Gozalbo et al., 1998;

Yan et al., 1998b
iC3b binding protein

(multiple candidates)
iC3b
Eigentler et al., 1989; Hostetter et al., 1990;

Alaei et al., 1993
Fucose binding protein

(1 5-kDa fragment)
Fucose-containing oligosaccharide
(blood group antigen?)
Cameron and Douglqs, 1996
GIcNAc or glucosamine
binding protein (190 kDa)
Host oligosaccharide-containing
GIcNAc or glucosamine
Enache et al., 1996
SAP (secreted aspartyl

proteinase)
Unknown (proteolytic modification

of host or fungus?)
Watts et al., 1 998
ALS gene family

ALSI
ALA1
Other proteins (38-kDa, 54-kDa
candidate species)
Unknown
Unknown
Fu et al., 1998
Gaur and Klotz, 1997
Unknown
Imbert-Bernard et al., 1995
Adhesin
Carbohydrate
Chitin
Factor 6 oligomannosaccharide
Protein
66-kDa fimbrial protein
Fibronectin binding protein
(multiple candidates)
ular-weight yeast cell mannoproteins average more than

600 mannose residues and those from germ tubes more
than 300 residues. In addition, single mannose residues
and short, unbranched manno-oligosaccharides may be
0-linked to protein through serine and threonine.
Mannoproteins are found throughout the cell wall and
appear to be the dominant component at the cell surface. Electron microscopic analysis shows a variable
number of cell wall layers (from 3 to 8) that seems to be
related to the technique used, the strain, and growth
conditions of the fungus (Cassone et al., 1973; Rico et al.,
1991). This layering appears to be the result of quantitative differences in the individual components in different
regions of the wall. Fimbriae, which may extend 110 to
300 nm, radiate from the surface (Fig. 2a; Yu et al., 1994a).
The fimbrial subunit appears to be a highly glycosylated
glycoprotein with an apparent molecular mass of 66 kDa
(Yu et al., 1994a).
The architecture of the yeast wall has been studied
more extensively in Saccharomyces cerevisiae, and a number
of observations suggest that the candidal cell wall will fit
the same model. In a recent study, material was isolated
from a cell wall digest that contained all of the major wall
362
components, 3-1,3-glucan, 3-1,6-glucan, chitin, and

mannoprotein (Kollar et al., 1997). The analysis of this
material suggested that 3-1,6-glucan with some f-I,3glucan branches may be linked to the reducing end of
chitin. Covalent attachment of mannoprotein to 3-1,6glucan is through a remnant of the mannoprotein GPI
(glycosyl phosphatidyl inositol) anchor. However, each
complex may not contain all four components, and the
proportion of cell wall polysaccharide involved in this
type of structure is unclear.
(B) C. ALBICANS ADHESINS
Adhesins are the fungal surface moieties that mediate

binding of C. albicans to other cells (host or microbial),
inert polymers, or proteins. Different experimental
approaches and reagents have been used to identify C.
albicans adhesins (also called binding proteins or receptors) and host ligands (sometimes also called receptors).
There is disagreement among some of these studies as
to the identity, number of candidal receptors for various
ligands, and the inhibitors of adherence (reviewed
recently in Fukazawa and Kagaya, 1997; Sturtevant and
Calderone, 1997; Chaffin et al., 1998). Our incomplete

10(3):359-383 (1999)
understanding of the factors that influence the adherence interactions is a likely source of apparently conflicting observations. Following are examples of five factors
with the potential to affect observations:
(1) Some C. albicans strains are more adherent than
others (Schmid et al., 1995b).
(2) Some strains possess adhesins with different
specificities (Critchley and Douglas, 1987a,b).
(3) In vitro growth conditions of the fungus-such as
temperature (Lee and King, 1983), medium composition
(Alloush et al, 1996; Yan et al., 1998b), carbon source
(McCourtie and Douglas, 1985; Gustafson et al., 1991), or
the presence of a specific inducer (Yan et al., 1998a)may alter the expression of an adhesin.
(4) Fungal cell viability may affect the extent of binding (Gorman et al., 1986).
(5) The binding capacity of exfoliated human cells
used in adherence assays may differ among donors and
from the same donor on different days (Sandin et al.,
1987b) and with hormonal status (Theaker et al., 1993).
Despite differences between some studies, the general conclusions are that C. albicans possesses multiple
adhesins and that there may be more than one adhesin
that recognizes a host ligand or cell. Most adhesins identified to date are mannoprotein, and, for individual
adhesins, both the protein and/or carbohydrate portions
have been implicated in adherence.
corneum model, three isolates from oral infections

adhered more than a commensal isolate (Law et al., 1997).
Removal of lipid from the stratum corneum led to doubling of the number of adhered organisms. Specific
epithelial lipids can modulate fungal adherence, since
binding was inhibited by fatty acids, sterols, and
ceramides and was unaffected by squalene, steryl esters,
cholesterol esters, and triglycerides. In a murine stratum
corneum model, yeast cells of C. albicans and C. stellatoidea
adhered in greater numbers than those of C. tropicalis,
while C. guilliermondii, C. krusei, and C. parapsilosis cells
showed little or no adherence (Ray and Payne, 1988). This
hierarchy of adherence was similar to that observed with
human epidermal corneocytes and BECs (Ray et al., 1984).
In the murine stratum corneum model, the adherent cells
acquired fibrils and strands of an amorphous material
between the yeast and corneocyte cell surface, formed
cavitations at the site, and produced hyphae that invaded
corneocytes distal to the yeast attachment (Ray and
Payne, 1988). Depletion of lipids had no effect on adherence in this study, but pepstatin, an inhibitor of the fungal secreted aspartyl proteinase, inhibited the formations
of cavities around the adherent cells. Epidermolytic proteases, likely including the secreted aspartyl proteinase,
have been isolated from strains recovered from patients
with cutaneous disease (El-Maghrabi et al., 1990).
Pepstatin, bovine brain gangliosides, and convalescent
human serum all reduced binding of yeast cells to corneocytes. Although there may be differences among
adhesins for corneocytes and BECs and vaginal epithelial
cells (VECs), it is likely that there are at least some common adhesins. It appears, therefore, that C. albicans chitin
and proteinase may be important in skin colonization.
(C) ADHERENCE TO SKIN

Skin is a site of normal colonization as well as infections
such as diaper rash and intertriginous candidiasis.

Infections usually occur in individuals with some loss of
normal skin defenses such as abrasion and maceration,
and yeast growth is promoted by a warm, moist environment (Samaranayake, 1990; Scully et al., 1994). Systemic
conditions such as diabetes, obesity, and various medical
treatments may also contribute to susceptibility to skin
and other mucocutaneous infections (Odds, 1988;
Samaranayake, 1990). C. albicans cells bind in vitro to corneocytes (keratinized cells of stratum corneum) from
individuals in these susceptible groups at twice the frequency with which they bind to corneocytes from healthy
individuals (Srebrnik and Segal, 1990). Amino sugars,
mannosamine, glucosamine, and galactosamine inhibited binding of C. albicans to human corneocytes and to
buccal epithelial cells (BECs) (Collins-Lech et al., 1984). A
chitin-soluble extract (CSE) also inhibited binding of C.
albicans to human corneocytes (Kahana et al., 1988). C. albicans cells exposed to nikkomycin, a chitin synthetase
inhibitor, had decreased chitin content and showed a corresponding decrease in adherence to BECs (Segal et al.,
1997). The site of adherence between the yeast cells and
epithelial cells labeled intensely with wheat germ agglutinin, a lectin-recognizing chitin. In a porcine stratum
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(4) Adherence to Oral Surfaces

The oral cavity presents a number of surfaces for C. albicans adhesion. These include BECs, the inert polymers of
dental prostheses, teeth, and other oral micro-organisms. Adherence to each of these surfaces and the modulating effect of saliva on adhesion will be discussed.
(A) ADHERENCE TO BECs

Exfoliated BECs are probably the best-investigated
human cell type in C. albicans adherence studies, and several adhesin/ligand interactions have been proposed
(Table 1). In interpreting the results of BEC adhesion
assays, one should note the following features: Fungal
strain and source of epithelial cells affect adherence
(Sandin et al., 1987b), the number of C. albicans cells that
bind to individual BECs is variable (Sandin et al., 1987a),
there are both binding and non-binding BECs (Gorman et
al., 1986; Polacheck et al., 1995), and both viable and nonviable C. albicans cells bind to BECs, with the non-viable
cells having a greater adherence (Gorman et al., 1986).
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The binding capacity of BECs from newborn full-term

infants for Candida is less than that of BECs from premature infants, school-age children, and adults, but increases over the infants' first few days (Davidson et al., 1984;
Cox, 1986; Polacheck et al., 1995). Adherence was greater
to BECs from children with oral infection or colonization
than to BECs from uninfected controls but increased
during a course of antibiotic therapy in previously uninfected children (Cox, 1983). Menstrual cycle affects
epithelial binding capacity, since BECs collected on day
5 showed a binding capacity higher than that of cells collected on day 15, 22, or 28 (Theaker et al., 1993). In one
study, VECs from the first and fourth weeks had a binding capacity higher than that of VECs from the second or
third week (Segal et al., 1984), while another study suggested that binding capacity peaked between the third
and fourth weeks (Bibel et al., 1987). VECs collected from
pregnant or diabetic women also bound more C. albicans
cells than those from non-pregnant or non-diabetic controls, and 'infection isolates' adhered better than 'colonizing isolates' (Segal et al., 1984). However, there was no
difference in the binding capacity of VECs from women
with recurrent vaginitis compared with healthy controls
(Trumbore and Sobel, 1986). Palatal epithelial cells from
acrylic-denture-wearers with non-insulin-dependent diabetes bound more fungal cells than did epithelial cells of
non-diabetic individuals (Dorocka-Bobkowska et al.,
1996). In another study, adherence to BECs from diabetic individuals was similar to adherence to BECs from normal individuals (Polacheck et al., 1995). Thus, adherence
to BECs is affected by many host factors, and hormonal
effects on adherence could be mediated by altering the
expression of adhesins on C. albicans cells or ligands on
host cells.
There is also variability in binding to BECs from different donors (Sandin et al., 1987b). Adherence differed
when epithelial cells were collected on different dates,
but gender was not a factor. C. albicans adhered in greater
numbers to BECs from AIDS patients than to BECs from
healthy individuals or transplant patients (Schwab et al.,
1997). C. albicans isolates from patients in the early stages
of AIDS adhered to BECs less well than did those from
healthy individuals. However, adherence of isolates
increased with the progression of AIDS until it exceeded
that of control isolates (Pereiro et al., 1997). Isolates from
immunocompetent patients with esophageal candidiasis
adhered better than isolates from patients who were
heavily colonized but not symptomatic (Wellmer and
Bernhardt, 1997). Although there were differences among
strains, isolates from candidiasis patients were more
adherent and formed germ tubes more rapidly than the
other isolates. Analysis of these results is complicated by
the fact that the adherence of strains from AIDS patients
has mostly been measured in vitro and may not correlate
364
to adherence in vivo for patients who are on courses of
antifungal drugs.
The effect of treating BECs and/or C. albicans cells
with antimicrobial agents on subsequent adherence has
been studied extensively. The consensus of opinion is
that treatment of BECs or yeast cells with any of a variety
of agents-including chlorhexidine, hexetidine,
dequalinium chloride, cetrimide, cetylpyridinium chloride, octenidine, pirtenidine, taurolidine, propamidine
isethionate, noxythiolin, and aqueous garlic extractreduced adherence (Gorman et al., 1986, 1987a,b; Tobgi et
al., 1987; Ghannoum, 1990; Ghannoum et al., 1990; Jones
and Fowler, 1994). Also, treatment of C. albicans with
propamidine isethionate, octenidine, pirtenidine, and
aqueous garlic extract reduced germ tube formation
(Jones and Fowler, 1994; Jones et al., 1997). Exposure to
antifungal drugs may also reduce adherence to epithelial
cells. Subinhibitory concentrations of amphotericin B,
nystatin, miconazole nitrate, and 5-fluorocytosine
reduced binding of C. albicans, C. tropicalis, and C. kefyr to
BECs, and the effect of amphotericin B and 5-fluorocytosine combined was greater than that of either alone
(Abu-el Teen et al., 1990). A one-week course of fluconazole also reduced the adherence of C. albicans to BECs
(Darwazeh et al., 1991). Drug treatment could be affecting
cell-surface charge, or wall and membrane biosynthesis
and structure.
Binding of C. albicans to exfoliated epithelial cells is
affected by growth conditions of the fungus and can be
inhibited by several reagents. Although there are some
differences among studies that may reflect the complexity of growth conditions and adhesin expression, there is
progress in characterizing the interactions and identifying the fungal adhesins and host receptors. Growth of C.
albicans in media containing glucose, sucrose, galactose,
xylitol, or maltose enhanced binding to BECs and HeLa
cells; maltose was the most effective and glucose the
least effective sugar (Samaranayake and MacFarlane,
1982). Growth in the presence of glucocorticoids, dexamethasone, or triamcinolone acetonide also increased
adherence to BECs (Ghannoum and Abu Elteen, 1987).
In one study, organisms grown at 250C were more adherent than those grown at 37C (Lee and King, 1983). Cellsurface hydrophobicity, which is increased at the lower
growth temperature, is suggested to contribute to, but
not be the predominant mechanism of, adherence to
BECs (Hazen, 1989). A decrease in hydrophobicity may
contribute partially to the decrease in binding following
treatment of C. albicans with cetylpyridium chloride, taurolidine, chlorhexidine acetate, or providone-iodine
(Jones et al., 1991, 1995). Another study demonstrated
that an increase in temperature during growth promoted
adherence, and, as with growth on different carbon
sources, this may be due to increased expression of an
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adhesin for a high copy number receptor (Staddon et al.,

1990).
Concanavalin A, a lectin-recognizing mannan, is an
inhibitor of adherence to BECs (Sandin and Rogers,
1982; Sandin, 1987; Macura and Tondyra, 1989). Glucose,
galactose, sucrose, or mannose enhanced adherence to
BECs, while xylose, ribose, fructose, maltose, lactose, or
raffinose had no effect on adherence (Macura and
Tondyra, 1989). Another study found no effect of galactose, N-acetylglucosamine (GIcNAc), ribose, or xylose
(Sandin, 1987). Thus, certain sugar residues may be
involved in a lectin-like adherence interaction or may
cross-bridge between adhesin and ligand. Lipids extracted from C. albicans or C. tropicalis inhibited binding to
BECs and involved individual phospholipids, sterols,
and steryl ester but not triacylglycerols or free fatty acids
(Ghannoum et al., 1986).
Several C. albicans cell wall proteins have been identified as adhesin candidates for epithelial cells. In one
study, a yeast cell wall extract fractionated by concanavalin A-affinity chromatography followed by ionexchange chromatography yielded a fraction that substantially inhibited yeast cell binding to BECs (ImbertBernard et al, 1995). This fraction contained four moieties, of which the 38- and 54-kDa proteins were suggested as adhesins. 0-linked mannoproteins may also be
involved in C. albicans adherence to epithelial cells. The C.
albicans CaMNTI gene encodes a mannosyl transferase
involved in 0-linked mannosylation, and a Camntl nullmutant showed reduced adherence to BECs (Buurman et
al., 1998).
Fibronectin was one of the first molecules to be suggested as a ligand recognized by a C. albicans adhesin
(Skerl et al, 1984). Both BECs and VECs stained with antifibronectin antibody, and yeast cells pre-treated with
fibronectin showed reduced binding to BECs and VECs
compared with untreated cells (Skerl et al., 1984; Kalo et
al., 1988). The complement fragment iG3b has also been
implicated as a ligand involved in epithelial and
endothelial cell adherence (Gustafson et al., 1991; Bendel
and Hostetter, 1993; Bendel et al., 1995; also see reviews
by Hostetter, 1994; Chaffin et al., 1998). Glucose-grown
cells express more iC3b receptor than glutamate-grown
cells and show increased binding to human umbilical
vein cells (HUVCs) (Gustafson et al., 1991). Antibody to
the human iC3b integrin receptor, iC3b, and several RGD
(arginine-glycine-aspartic acid)-containing peptides
from iC3b reduced binding of C. albicans to HUVCs or
HeLa cells (Bendel and Hostetter, 1993). After growth of
HeLa cells in serum-free medium, iC3b and fibronectin
were detected on the cell surface, and treatment with
anti-C3 antibody, but not anti-fibronectin antibody,
reduced adherence of C. albicans. although the reverse
effect was observed with C. tropicalis. The candidates for
fibronectin and iC3b adhesin(s) are described in more

detail below.
The secreted aspartyl proteinases (SAPs) also appear
to contribute to C. albicans adherence to BECs and other
substrates (Ghannoum and Abu Elteen, 1986; ElMaghrabi et al., 1990; Watts et at., 1998). The SAP gene
family consists of at least seven members encoding 42to 45-kDa aspartyl proteinases (Hube et al., 1994; Monod
et al., 1994). The expression of proteinase isozymes
depends on the strain, cellular morphology, and environmental factors (White and Agabian, 1995). Strains deficient in one or more of these genes have been constructed. Deletions in SAPI, SAP2, or SAP3 reduced
adherence of the organism to poly-L-lysine, an extracellular matrix (ECM) preparation, or (slightly) to BECs
(Watts et al., 1998). However, a triple Asap 4-6 mutant
showed decreased adherence to the first two substrates
but increased adherence to BECs. Pepstatin inhibited
binding of the parental strain to all three substrates. In
addition to any direct effect on adhesion, proteinases
may act on the yeast surface to modify adhesins or host
surfaces to expose ligands.
BEC glycosphingolipid is also an adherence target
for C. atbicans. Several pathogenic yeasts, including C.
albicans, bind to lactosylceramide ltGal( 1 -4)3Glc(l - )Cerl
(limenez-Lucho et al., 1990). C. albicans fimbriae bound to
BECs and reduced the binding of C. albicans yeast cells to
BECs (Yu et al., 1994b). Purified fimbriae bind to an asialo3Gal(1 -3)f3GalNAc( 1GM, Igangliotetraosylceramide:
on microtiter
immobilized
1-I
)Cerl
4)3Gal( l-4)f3Glc(
inhibited up
was
BECs
to
fimbriae
of
plates. The binding
also binds
aeruginosa
to 80% by asialo-GMP. Pseudomonas
adhesins
the
and
pili,
to this glycosphingolipid through
a comshare
to
from P. aeruginosa and C. albicans appear
1994c,
et
al.,
mon binding domain (adhesintope) (Yu
in
P.
1996). Antibodies to this domain the aeruginosa pilus
protein inhibit binding of both organisms to BECs, and a
peptide derived from this region is also inhibitory.
The presence of candidal lectin-like epithelial
adhesins that recognize L-fucose or GlcNAc has been
reported (Critchley and Douglas, 1987a,b). Fucose
inhibits binding of some strains to BECs, and glucosamine or GlcNAc inhibits the binding of other strains,
suggesting strain-specific receptors. Synthesis of the
lectin-like material increased when organisms were
grown on galactose (McCourtie and Douglas, 1985).
Extracellular material recognizing L-fucose inhibited
binding of the homologous strain. Fucose has been
shown to bind to yeast and hyphal cells with approximately 2 x 107 binding sites per hyphal cell, mostly located adjacent to the hyphal tip (Vardar-Unlu et al., 1998). A
fragment of an L-fucose-binding protein was purified by
affinity chromatography with the blood group H trisaccharide antigen that terminates in fucose, and it was sug-
(9)Gi e rlBo e
10(3)-.359-383 (1999)
103
365
gested that blood group antigens may act as epithelial

cell receptors for C. albicans (Cameron and Douglas,
1996). The purified fragment inhibited binding to BECs
by up to 80%. Binding to an esophageal cell line (Het-l)
is partially mediated by a lectin-like interaction (Enache
et al., 1996). Yeast cells grown on galactose adhere better
than those grown on glucose, and GlcNAc or glucosamine reduce binding by about 40%. A 190-kDa glycoprotein detected in cell wall extracts of galactosegrown cells was postulated to be responsible for the
increased adherence (Enache et al., 1996).
The serotype A determinant, factor 6, of C. albicans
mannan has also been implicated in epithelial adherence (Miyakawa et al., 1992). A mutant strain deficient in
the factor 6 determinant, or serotype B strains, showed
reduced adherence to BECs compared with non-mutant
serotype A strains. Mannan from the wild-type strain and
anti-factor 6 antibody inhibited adherence to BECs.
A genetic approach has yielded two candidate C. albicans adhesins for epithelial cells. The fact that S. cerevisiae
cells adhere to a variety of surfaces significantly less well
than do C. albicans cells has been used by several groups
to screen C. albicans genomic libraries for sequences that
confer adherence on the non-adherent yeast. Separate
screens have identified two members of a family of related genes. Members of the C. albicans ALS (agglutinin-like
sequence) family are related to S. cerevisiae agglutinin
genes that mediate cell-cell interactions during mating
of haploid cells (Hoyer et al., 1995). Als proteins have a
central domain of a tandemly repeated motif that is rich
in serine, threonine, and proline. The sequence of ALSI
carries a signal for a GPI (glycosyl phosphatidyl inositol)
anchor. Another member of the family, ALAl, was isolated by the screening of a library for sequences that conferred adherence to ECM (Gaur and Klotz, 1997).
Transformed yeast cells bound to fibronectin, laminin,
and collagen IV. In addition, adherence to BECs was
increased, suggesting that the adhesin may be multifunctional, recognizing multiple ligands, and mediating
adherence to different tissues. More recently, ALS1 has
again been isolated in a screen of a C. albicans genomic
library for sequences conferring increased adherence to
endothelial cells (Fu et at., 1998). Expression of ALS1 also
substantially increased binding of S. cerevisiae to the FaDu
oropharyngeal epithelial cell line. More definitive evidence for the role of these proteins in candidal adherence awaits further analysis in that organism.
Nonetheless, members of the Als protein family are certainly candidates for adhesins that mediate adherence of
C. albicans in the oral cavity.
In addition to physical immobilization, adherence of
Candida cells to BECs may lead to alterations in fungal
gene expression (Bailey et al., 1995). Analysis of proteins
synthesized by C. albicans three hours following adhesion
366
to BECs showed that proteins of 52-56 kDa differed in the

extract of attached yeast cells compared with those from
unattached yeast or from BECs alone. Furthermore, anti-
phosphotyrosine antibodies recognized 54-kDa and 60kDa species from the attached cells but not from cells in
control cultures. These results suggest that contact of C.
a surface may activate signaling pathways
that result in the expression of adhesins. Some C. albicans
strains demonstrate the phenomenon of phenotypic
switching (Soll, 1997). It is postulated that a 'master
switch' is responsible for turning off one set of genes and
switching on another set, some of which may be involved
in virulence. It is possible that contact with a particular
surface activates a set of genes involved in adherence to,
and penetration of, that surface.
albicans with
(B) ADHERENCE TO INERT POLYMERS

C. albicans adheres to a variety of materials found in medical devices, such as catheters and oral prostheses. This
adherence may promote colonization and infection. C.

albicans is able to form biofilms on the surfaces of these
materials (reviewed in Chaffin et al., 1998). In addition,
colonization may contribute to the deterioration of the
devices (Marcuard et al., 1993; Gottlieb and Mobarhan,
1994; Busscher et al., 1997; van Weissenbruch et al., 1997),
and adherent organisms may be less susceptible to antifungal drugs (Kayla and Ahearn, 1995; Hawser, 1996).
Most studies have focused on oral devices which may
contain multiple materials. Since these studies used different fungal growth conditions, different adherence
assays, and different methods of analysis, the results
cannot be compared directly.
Hydrophobicity has been frequently, but not universally, implicated as a major factor in the adherence of
Candida species to inert polymers. The more hydrophobic
species C. tropicalis, C. glabrata, and C. krusei adhered more
to these polymers, including those found in denture
resin materials, than the less hydrophobic C. albicans, C.
stellatoidea, and C. parapsilosis (Klotz et al., 1985; Minagi et
al., 1985, 1986; Miyake et al., 1986). Isolates of C. krusei, an
emerging pathogen, showed variable but greater
hydrophobicity than C. atbicans isolates, and there was a
correlation between hydrophobicity and adherence to
HeLa cells but not to denture acrylic (Samaranayake et
al., 1995). This suggests that factors other than
hydrophobicity might contribute to the hierarchy of virulence among Candida species. In an earlier study, isolates
of C. albicans showed greater adherence to acrylic than
isolates of other species (Segal et al., 1988). Adherence is
increased on rough acrylic and silicone rubber surfaces
compared with smooth surfaces (Verran and Maryan,
1997). The acrylic base for dentures supported less
adherence of C. albicans than tissue conditioners and a
soft liner (Okita et al., 1991).
Crit
Crit Rev
Rev Oral
Oral Biol
Biol
Med
Med
lO(3):359-383
(1999)
10(3):359-383 (1999)
As dental prostheses are exposed to saliva and oral

bacteria, a complex biofilm develops to which C. albicans
cells can adhere. The fungus is present in biofilms in various morphological forms, and extracellular material
may also be present (Hawser and Douglas, 1994). The
extent of biofilm formation is dependent on the nature of
the inert material; the greatest biofilm formation was
found on latex, which is frequently used in urinary
catheters, followed by silicone elastomer and polyvinyl
chloride, often found in central venous catheters.
Formation of a biofilm was least on polyurethane and
100% silicone. In vitro, gentle liquid flow increased the
formation of the extracellular matrix material, in which
the organism was embedded, compared with static conditions (Hawser et al., 1998).
As with adhesion to BECs, treatment of either dental
acrylic or C. albicans cells with antimicrobial agents
affects adhesion. Incubating acrylic with chlorhexidine
gluconate, amphotericin B, nystatin, but not a histidine
polypeptide, reduced binding to the polymer (McCourtie
et al., 1985, 1986a,b; Spiechowicz et al., 1990). Exposure of
stationary-phase cells to chlorhexidine for a short period, or growth of C. albicans in a sublethal concentration of
chlorhexidine, reduced the adherence of the cells compared with unexposed cells, and the treated cells were
more susceptible to the action of :3-glucanase. This suggests an effect of chlorhexidine on the fungal cell wall.
When C. albicans was grown in subinhibitory concentrations of antifungals, exposure to azalomycin F and
aculeacin A increased subsequent adherence to acrylic,
while exposure to miconazole, ketoconazole, and
amphotericin B did not alter adherence (Miyake et al.,
1990). Exposure to drugs did not change cell-surface
hydrophobicity, while the negative charge of the cell surface decreased in the more adherent cells, suggesting
that a decrease in electric repulsive force enhanced binding. Growth of C. albicans, C. krusei, C. kefyr, C. tropicalis, C.
parapsilosis, and C. guilliermondii in subinhibitory concentrations of sodium hypochlorite resulted in subsequent
reduction in adherence of all C. albicans strains and most
other species to polystyrene and BECs (Webb et al.,
1995). Growth in hypochlorite appeared to increase the
numbers and amounts of certain proteins in cell wall
extracts from C. albicans and C. parapsilosis, again indicating alterations in the cell wall composition.
Several surface mannoproteins, among them
hydrophobic proteins, have been suggested as adhesin
candidates for plastics (reviewed by Fukazawa and
Kagaya, 1997; Chaffin et al., 1998). Yeast cells grown in
galactose were more adherent to acrylic than those
grown in medium containing glucose, sucrose, fructose,
or maltose (McCourtie and Douglas, 1981). Material
found in the growth medium, when used to pre-treat
acrylic or BECs, promoted adherence of C. albicans cells to
10(3
359383(199)
10(3)-359-383 (1999)
acrylic but reduced adherence to BECs (McCourtie and

Douglas, 1985). When germ tubes that adhered to polystyrene were physically removed, several mannoproteins
were subsequently solubilized from the plastic (Tronchin
et al., 1988). Two major constituents of 60 and 68 kDa and
two minor constituents of high molecular mass (. 200
kDa) were obtained. While the relationship of the smaller species to similar-sized proteins described below as
recognizing other ligands is unknown, the size similarity
has supported conjecture that there may be multi-functional adhesins recognizing a variety of ligands. A 58-kDa
and a 37-kDa protein which bind fibrinogen and laminin,
respectively, also bind to plastic and have been suggested to possess hydrophobic domains (Lopez-Ribot et al.,
1991, 1995). Among extracted cell wall proteins, there are
many that have hydrophobic domains. Analysis of proteins adsorbed to latex beads showed a spectrum of proteins in the 20- to 67-kDa range that may be more abundant in extracts from germ tubes (Lopez-Ribot et al.,
1991). Hydrophobic interaction chromatography of
extracted proteins suggested that the hydrophobic proteins were usually smaller (< 50 kDa) than the
hydrophilic proteins (> 90 kDa), perhaps reflecting the
extent of glycosylation (Hazen and Hazen, 1992, 1993;
Hazen and Glee, 1994). Hydrophilic cells exhibit a dense
layer of fibrils not observed on hydrophobic cells, and it
has been proposed that this layer masks the hydrophobic species. In keeping with this suggestion, the abundance of the acid-labile phosphodiester-linked mannooligosaccharides was less in mannan from hydrophobic
cells than in that from hydrophilic cells (Masuoka and
Hazen, 1997).
(C) ADHESION TO TEETH

The mouth is a unique part of the body in that it contains
exposed mineralized tissues, in the form of teeth. Beads
of crystalline hydroxyapatite (HA) have been used in
adhesion assays as a model for studying microbial adhesion to tooth surfaces (Clark et al., 1978). C. albicans cells
do not bind well to hydrated HA beads, but adherence is
stimulated greatly by pre-incubation of the beads with
either whole or parotid saliva ( Cannon et al., 1995b;
O'Sullivan et al., 1997). Adherence to saliva-coated
hydroxyapatite (SHA) beads is strain-specific (O'Sullivan
et al., 1997), and strains more frequently associated with
candidiasis adhere significantly better to SHA beads
than do less pathogenic strains (Schmid et al., 1995b).
(D) CO-ADHERENCE
C. albicans cells co-adhere with several species of oral
bacteria, including Streptococcus gordonii, S. mutans, S. oralis,
S. sanguis, S. salivarius, and Actinomyces species (Richards
and Russell, 1987; Branting et al., 1989; Jenkinson et al.,
1990; Holmes et al., 1995b; Millsap et al., 1998). The
Cit Rv Orl Bd Me
Crit Rev Oral Biot Med
36
367
growth conditions for the bacteria, however, can affect

co-adherence (Richards and Russell, 1987; Millsap et al.,
1998), and some assays do not take into account the
kinetics associated with the larger size of yeast cells
(Millsap et al., 1998). Colonizing acrylic with oral streptococci in the presence, but not in the absence, of sucrose
enhanced binding of C. albicans (Richards and Russell,
1987; Branting et al., 1989). C. albicans bound in greater
numbers to acrylic pieces coated with S. sanguis, S.
mutans, or S. sobrinus than to uncoated acrylic, but in this
case, pre-incubation of the bacteria with sucrose to
induce synthesis of extracellular polymers did not
increase binding (Vasilas et al., 1992). Protein-protein and
lectin interactions have been proposed for the adhesive
interactions between Candida and bacteria, although
hydrophobic and electrostatic interactions may also take
part (Millsap et al., 1998). Both carbohydrate (Holmes et
al., 1995b) and protein molecules (Holmes et al., 1996)
that act as C. albicans receptors have been identified on
the surface of S. gordonii. A carbohydrate containing
rhamnose, glucose, GlcNAc, and galactose, isolated from
the cell walls of S. gordonii cells, acted as a receptor for C.
albicans adherence in an in vitro assay (Holmes et al.,
1995b). Gene disruption experiments have shown that C.
albicans adherence to bacteria is multifactorial, and interactions involving the S. gordonii cell-surface polypeptides
CshA, CshB, SspA, and SspB contribute to co-adherence
(Holmes et al., 1996). The co-adherence of C. albicans with
oral bacteria is species-specific. Pre-treating BECs or denture acrylic with S. salivarius, Escherichia coli, or Porphyromonas
gingivalis reduced subsequent adherence of C. albicans cells
(Nair and Samaranayake, 1996a,b). Also, in one report, a
biofilm of S. gordonii reduced adherence of most C. albicans
strains and other species to polystyrene (Webb et al.,
1995). This would suggest that C. albicans recognizes specific receptors on certain oral bacteria which are expressed
under particular growth conditions.
(E) ADHERENCE TO SALIVA MOLECULES

In the oral cavity, proteins from saliva selectively adsorb
to surfaces to form acquired pellicles. The acquired
enamel pellicle has been particularly well-studied, and
after two hours' formation it has been found to contain
immunoglobulins, mucin, at-amylase, cystatins, prolinerich proteins, lysozyme, glucosyltransferases, albumin,
fibrinogen, and serum components (Kraus et al., 1973;
Rolla et al., 1983; Al-Hashimi and Levine, 1989; Jensen et
al., 1992; Edgerton et al., 1996). The composition of the
pellicle depends on the underlying surface (Edgerton et
al., 1996) and the composition of the saliva (Jensen et al.,
1992; Edgerton et al., 1996). The intra-oral composition of
saliva varies (Sas and Dawes, 1997), and this affects the
pellicles formed at different sites, and hence the pattern
of microbial colonization. Since all surfaces are coated
with a salivary pellicle, it is reasonable to suppose that

microbial adherence interactions involve adsorbed saliva
molecules. Saliva pellicles increase the adherence of C.
albicans cells to HA beads (Cannon et al., 1995b), polymethylmethacrylate (Edgerton et al., 1993), and to S. gordonii cells (Holmes et al., 1995a) (Fig. 2b). Adherence of C.
albicans was greater to dental acrylic coated with whole
saliva than to uncoated acrylic, and a coating of parotid
saliva stimulated adherence more than a coating of submandibular-sublingual saliva (Vasilas et al., 1992). In an
earlier study, however, adhesion to acrylic was reduced
by an 18-hour whole-saliva pellicle (Samaranayake et al.,
1980). Also, coating of acrylic surfaces with whole saliva
reduced the contact angle and decreased the binding of
hydrophobic Candida strains, while the adherence of
more hydrophilic C. albicans was unaffected (Miyake et al.,
1986). Adherence to two experimental silicone soft-lining materials was less than to a commercial product or
the acrylic base, varied with the strains, and was reduced
when the materials were coated with saliva (Waters et al.,
1997). In another study, however, coating soft liners with
saliva or serum increased adherence of C. albicans and
biofilm formation, although the effect varied with the
material and protein source (Nikawa et al., 1997). Coating
also increased firm colonization and hyphal invasion,
although the plasticizer used affected cavitation.
Incubating polymethylmethacrylate beads with submandibular-sublingual saliva enhanced C. albicans binding compared with coating them with parotid saliva
(Edgerton et al., 1993). Binding was reduced by treatment
of yeast cells with protease or glycosidase or incubation
with mannose or galactose. Interestingly, C. albicans cells
do not detectably bind proteins from saliva in the fluid
phase, apart from small amounts of mucin MG 1 and MG2
(Edgerton et al., 1993; Newman et al., 1996), which would
explain why added saliva did not inhibit adherence of C.
albicans to SHA beads (Cannon et al., 1995b). This indicates that C. albicans may have specific adhesins that recognize cryptitopes on saliva molecules that are exposed
when the molecules adsorb to surfaces (Fig. 2b). Such
adhesins would promote colonization and prevent saliva-mediated aggregation and clearance from the oral
cavity.
In order to identify the saliva proteins to which C.
albicans cells adhere, investigators have developed blot
overlay assays (Newman et al., 1996; O'Sullivan et al.,
1997), in which saliva proteins are separated by SDS
polyacrylamide gel electrophoresis, electroblotted onto
nitrocellulose membranes, and incubated with either
radiolabeled (O'Sullivan et al., 1997) or fluorescently
labeled (Newman et al., 1996) yeast cells.
Autoradiography or photography, respectively, reveals
the protein bands to which the cells bind. These studies
have identified basic proline-rich proteins, including IB-
ilMdl()3933(99
GrtRvOa ~
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368~~~~~~~
368
10(3):359-383 (1999)
6 (O'Sullivan et al., 1997) and Psi (Newman et al., 1996),

as receptors for C. albicans adhesion.
(5) Growth
In order to maintain Candida populations in the oral cavity, cells must grow and multiply at a rate at least equal
to that of clearance. The growth rate of C. albicans in saliva is too low to be measured accurately, due to carbon
source limitation (Samaranayake et al., 1986), which is
presumably caused by the large number of bacteria in
saliva. Therefore, any metabolic activity that helps C. albicans acquire carbon or nitrogen will aid its growth and
survival in the oral cavity. C. albicans secretes aspartyl proteinases, which are believed to contribute to the organism's virulence in several ways (Hoegl et al., 1996).
Tissue destruction may aid fungal penetration, but this
process could also release peptides as a source of nitrogen or carbon. The proteinase Sap2, for example,
degrades gastrointestinal mucin, and mucin can act as a
sole nitrogen source for C. albicans (Colina et al., 1996). In
addition, C. albicans secretes the hydrolytic enzyme Nacetylglucosaminidase (also called hexosaminidase),
which cleaves chitobiose, the dimer of GIcNAc, into two
molecules of GIcNAc (Sullivan et al., 1984; Niimi et al.,
1997a). C. albicans can use GlcNAc as either a carbon or
nitrogen source. N-acetylglucosaminidase activity is
shown by C. albicans and C. dubliniensis and to a lesser
extent by C. tropicalis cells (Niimi and Cannon, unpublished observation), species found relatively frequently in
the oral cavity. It is tempting to speculate that a function
of this enzyme may be to cleave terminal GIcNAc residues
from host glycoproteins, and that this scavenging activity
gives these Candida species a selective growth advantage.
Competition with other oral micro-organisms for
nutrients, such as glucose, affects the growth rate of
Candida cells. It is recognized that antibiotic treatment,
which reduces the number of oral bacteria, is a predisposing factor for oral candidiasis (Samaranayake, 1990).
Oral bacteria are present in most oral sites at concentrations much higher than C. albicans, and so the Candida
cells must compete with them for adhesion sites and
nutrients, and be exposed to bacterial toxins and byproducts.
(6) Evading Host Clearance Mechanisms

A major factor influencing the balance among clearance,
colonization, and candidiasis is the interaction between
C albicans cells and the host defenses (Cannon et al.,
1 995a). Immune system defects are a major risk factor for
candidiasis. Innate defenses include the epithelial barrier and anti-candidal compounds in saliva such as
lysozyme (Tobgi et al., 1988), histatins (Xu et al., 1991),
lactoferrin (Nikawa et al., 1993), and calprotectin (Muller
et al., 1993; Challacombe, 1994). Acquired immunity
lO(3:3593831999
10(3):359-383 (1999)
includes the production of immunoglobulins and, if tissues are penetrated, the involvement of macrophages
and polymorphonuclear leukocytes (Challacombe, 1994).
The major immunoglobulin in saliva is secretory IgA
(SIgA); serum immunoglobulins enter the saliva via the
gingival crevicular fluid, but are present at low concentrations. SIgA does not fix complement efficiently; its
major role is the agglutination of micro-organisms,
which are then swallowed more easily. Anti-Candida SIgA
can be detected in saliva, and its concentration is
increased in whole or parotid saliva from HIV-positive
individuals, but reduced in AIDS patients, suggesting
that a compensatory response is overcome with progressive immunodeficiency (Challacombe and Sweet, 1997).
C. albicans can be ingested by neutrophils and
mononuclear phagocytic cells (for a review of interactions with macrophages, see Vazquez-Torres and Balish,
1997). The interactions between these cells and C. albicans appear to involve both opsonic and non-opsonic factors. Components from the classic and alternative complement pathways can also enhance phagocytosis by
macrophages and neutrophils (Solomkin et al., 1978;
Marodi et al., 1991). C. albicans activates the alternate
pathway of complement, and both iC3b and C3d fragments can bind to C. albicans (adhesins for these fragments are discussed below). A candidal-protective mechanism has been proposed in which fungal binding of
iC3b blocks neutrophil CR3 recognition of iC3b and
phagocytosis of iC3b-coated C. albicans is reduced. Yeast
cells coated with an anti-human CR3 antibody, that
blocked the candidal binding protein, were phagocytosed by neutrophils to a greater extent than uncoated
cells (Gilmore et al., 1988). The clumping of C. albicans
cells coated with C3 fragments has also been proposed
as a candidal-protective effect, since these aggregates
are too large to be phagocytosed (Heidenreich and
Dierich, 1985). On the other hand, host protection is
postulated for the binding of serum vitronectin, since
Candida cells coated with vitronectin show enhanced
binding to macrophages and phagocytosis (Limper and
Standing, 1994).
Macrophage mannose receptors also mediate the
adherence of C. albicans (reviewed by Vazquez-Torres and
Balish, 1997). Binding of C. albicans to murine spleen and
lymph node tissue is primarily to macrophages (Kanbe et
al., 1993). A (31,2-linked mannotetraose in the acid-labile
C. albicans mannan as well as an acid-stable structure
were identified as adhesins (Li and Cutler, 1993; Kanbe
and Cutler, 1994). A monoclonal antibody to (1,2-linked
oligomannosaccharide, but not a monoclonal antibody
to the acid-stable mannan epitope, in the presence of
complement, enhanced phagocytosis of yeast cells by
neutrophils (Caesar-TonThat and Cutler, 1997). Soluble
mannan can inhibit phagocytosis of complement-C3-
Crf Re Ora Bil Me

Crit Rev Oral Biot Med
36
369
coated C. albicans by macrophage (Kolotila et al., 1987).

Thus, C. albicans phagocytosis may be mediated by either
the complement-dependent or mannose receptor pathways. The effect of mannan on the complement-mediated pathway, however, suggests that the pathways may
interact physiologically or physically. C. albicans has
developed other ways of evading the innate and the
acquired immune system. The C. albicans cell wall mannoproteins proposed to be receptors for SIgA binding are
released into the medium as yeast cells produce hyphae
(Ponton et al., 1996). The shedding of these receptors may
enable the hyphae to escape clearance. In addition, the
immunoglobulins present in saliva, including SIgA, IgG,
and IgM, are substrates of C. albicans secreted aspartyl
proteinase (Ruchel, 1986; Reinholdt et al., 1987).
(A) FINDING BETTER ENVIRONMENTS

C. albicans will grow more quickly and reach higher cell
concentrations in environments with less effective clearance mechanisms and better nutritional supply. Candida
cells have an array of mechanisms (virulence factors)
which enable them to colonize new environments, a
process often involving tissue penetration. Polarized
hyphal growth facilitates directional growth toward a different environment, and thigmotropism or contact sensing (Sherwood et al., 1992) could allow the hyphae to
invade tissues. C. albicans cells also secrete a number of
hydrolytic enzymes which may play a role in tissue
destruction and penetration. Phospholipase or N-acetylglucosaminidase production by C. albicans strains, for
example, correlated with virulence in mouse infection
models (Jenkinson and Shepherd, 1987; Ibrahim et al.,
1995). Many workers have investigated the role of secreted aspartyl proteinase isozymes in the pathogenesis of
candidiasis, and demonstrated their expression in vivo
(Borg and Ruchel, 1988; Ray and Payne, 1988; ElMaghrabi et al., 1990; De Bernardis et al., 1995; Hoegl et al.,
1996; Borg-von Zepelin et al., 1998). In addition to playing
a role in adherence, as discussed above, secreted proteinases may aid in tissue destruction and penetration.
Penetration of tissues brings C. albicans into intimate
contact with other cellular structures and host molecules
which could act as adhesion receptors. Tissue penetration also often involves breaching endothelial barriers
with consequential endothelial cell injury (Filler et al.,
1995). Depletion of endothelial cell iron reduces phagocytosis of the fungus and results in less cell injury (Fratti
et al., 1998). Phagocytosis and subsequent injury is also
reduced by treatment of endothelial cells with gamma
interferon (Fratti et al., 1996). Migration across an
endothelial layer is facilitated by hyphal formation (Zink
etal., 1996).
Several potential adhesins and ligands that mediate
binding of the fungus to endothelial cells have been
370
identified and may share identity with molecules

involved in epithelial adherence (reviewed by Hostetter,
1994; Fukazawa and Kagaya, 1997; Chaffin et al., 1998).
The iC3b binding protein(s) discussed below contributed
to adherence to umbilical vein endothelium. Two monoclonal antibodies that recognize human integrin subunit
tm partially inhibited adherence (Gustafson et al., 1991).
Adherence to cultured human dermal microvascular
endothelial cells was also reduced by treatment with an
anti-human CR3 monoclonal antibody (Lee et al., 1997).
Fibronectin has been observed, by indirect immunofluorescence, on endothelial cells as well as on epithelial
cells (see above). Fibronectin was detected on rabbit aortic valves in a model of non-bacterial thrombotic endocarditis (Scheld et al., 1985). C. albicans and C. tropicalis,
which are often isolated from infections, bound significantly better to fibronectin in vitro than the infrequently
isolated C. krusei. During the analysis of adherence to
endothelial monolayers, it was noted that C. albicans
adhered preferentially to subendothelial ECM (Klotz,
1987; Klotz and Maca, 1988). The candidal binding proteins for iC3b and fibronectin are discussed below.
(B) ADHERENCE TO ECM AND SERUM PROTEINS

C. albicans binds to several host proteins found in serum
and in ECM (Table 2; reviewed by Hostetter, 1994;
Fukazawa and Kagaya, 1997; Sturtevant and Calderone,
1997; Chaffin et al., 1998). Serum proteins that bind to the
fungus include serum albumin, transferrin, fibrinogen,
and the complement C3 fragments, C3d and iC3b
(Heidenreich and Dierich, 1985; Bouali et al., 1986; Page
and Odds, 1988). ECM components that bind to the fungus include fibronectin, laminin, entactin, collagen type
I and type IV, and vitronectin (Skerl et al., 1984; Bouchara
et al., 1990; Klotz, 1990; Jakab et al., 1993; Lopez-Ribot and
Chaffin, 1994). While the host ligands have been identified, less progress has been made with the identification
of the fungal adhesins, many of which appear to be
expressed more abundantly on the surfaces of germ
tubes than on yeast cells (Heidenreich and Dierich, 1985;
Bouali et al., 1986; Bouchara et al., 1990; Lopez-Ribot and
Chaffin, 1994). Some adhesins may recognize multiple
ligands, since similar-sized proteins have been identified
as potential adhesins for several ligands. Differences in
adhesin identification among various studies further
complicate the issue.
The interactions between human serum albumin and
transferrin and C. albicans have not been studied extensively. The two proteins were observed by indirect
immunofluorescence to bind preferentially to germ
tubes (Page and Odds, 1988). More recently, binding of C.
albicans cells to bovine serum albumin, immobilized on
microtiter plates, was reported, and binding was affected
by pre-incubation of the yeast with alanine, proline, and
Med
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TABLE 2
Oral Ligands for C. albicans Adhesion, and Possible Interventions to Prevent Colonization
Adhesion Ligand
Type of Interaction
Reference
Possible Interventionsa
Protein-protein, lectin, hydrophobic,
CHOb (e.g., CSEC), peptide

Hazen, 1989; Macura
and Tondyra, 1989;
Jimenez-Lucho et al., 1990;
Yu et al., 1 994a,b,c; Imbert-Bernard
et al., 1995; Cameron and
Douglas, 1996
Surface modification
Klotz et al., 1985; McCourtie
Hydrophobic, glycoprotein-acrylic
Dental acrylic
and Douglas, 1985;
Minagi et al., 1985
?CHO
Holmes et al., 1995b, 1996;
Oral bacteria
Lectin, protein-protein
Millsap et al., 1998
?CHO
Newman et al., 1996;
Adsorbed salivary proteins Lectin, ?protein-protein
O'Sullivan et al., 1997
Peptide
Hosteffer et al., 1990; Alaei
Protein-protein
iC3b
et al., 1993
Peptide
Skerl et al., 1984; Klotz et al.,
ECM proteins: Fibronectin Protein-protein, ?lectin
1993; Gozalbo et al., 1998;
Yan et al., 1998a
Bouchara et al., 1990; Gozalbo Peptide
Protein-protein
Laminin
et al., 1998; Yan et al., 1 998a
L6pez-Ribot and Chaffin, 1994 Peptide
Entactin
Protein-protein
Klotz et al., 1993; Chaffin et al., Peptide
Protein-protein
Collagen
1998
?CHO
Vitronectin Protein-protein, lectin
Limper and Standing, 1994;
Olson et al., 1996
a Non-specific interventions and those involving multiple interactions include antimicrobial mouthwashes.
b Carbohydrate (monosaccharides or oligosaccharides).
c Chitin-soluble extract.
BEC
fimbrial glycoprotein-BEC
glycosphingolipid
leucine but not with other amino acids (Hawser and

Islam, 1998). Human fibrinogen binds extensively to
germ tubes, while binding to yeast cells appears to
depend on growth conditions (Bouali et al., 1987; Page
and Odds, 1988). The major protein that interacted with
fibrinogen had a molecular mass of 68 kDa and also
bound to plastic, laminin, and C3d (Tronchin et al., 1988;
Annaix et al., 1990; Bouchara et al., 1990). A 58-kDa protein, encoded by FBP1, is also a fibrinogen-binding protein, but it does not appear to recognize the other ligands (Casanova et al., 1992; Lopez-Ribot et al., 1997). The
58-kDa fibrinogen-binding protein is modified by covalent attachment of the ubiquitin polypeptide (Seputlveda
et al., 1996), contains epitopes or sequences from a type
IV collagen molecule (Seputlveda et al., 1995), and is
expressed in vivo (L6pez-Ribot et al., 1996). The fibrinogen-binding species are distributed heterogeneously on
the cell surface, as determined by transmission, scanning electron, and confocal fluorescence microscopy
10(3):359-383 (1999)
(Bouali et al., 1987; Casanova et al., 1992; Martinez et al.,

1994). Binding of C. albicans to platelets appears to be
mediated via the interaction with fibrinogen (Robert et al.,
1996). Since fibrinogen can be a component of the
enamel pellicle (Kraus et al., 1973), it may also be a receptor for C. albicans adherence in the oral cavity.
C. albicans germ tubes have the ability to rosette antibody-sensitized erythrocytes coated with C3d or iC3b
(Heidenreich and Dierich, 1985). Functional and antigenic similarities between the fungal and mammalian
proteins that bind these moieties have led to frequent
use of terminology adopted from mammalian systems.
The fungal binding proteins are sometimes referred to as
an integrin analog or CR3 (iC3b binding proteins) and
CR2 (C3d binding protein). The receptor for iC3b may
play a role in adherence to epithelial and endothelial
cells, as discussed above. Antibodies that recognize subunits of human integrins which bind iC3b react with the
fungal cell surface. Using an anti- aXm antibody and fluo-

371
rescence flow cytometry, Gilmore et al. (1988) observed a

low level of receptor expression on yeast cells that was
affected by the concentration of glucose in the growth
medium and was strain-specific. There is no consensus
on the identity of the iC3b binding protein(s), since various studies implicate different components, including
165-, 130-, 66-, 55-, and 42-kDa proteins (Eigentler et al.,
1989; Hostetter et al., 1990; Alaei et al., 1993).
Oligonucleotide probes based on the postulated similarity to integrins were used to isolate a candidal integrin
homologue Intlp (Gale et al., 1996). Although it has limited similarity to integrins, the deduced Intlp sequence
contains a membrane spanning region and divalent
cation-binding motifs. Expression of the gene in S. cerevisiae resulted in aberrant cell morphology with formation
of germ-tube-like structures (Gale et al., 1998). A mutant
strain deficient in expression of this gene exhibited
reduced binding to HeLa cells, reduced hyphal formation
under some conditions, and reduced virulence in mice.
Several hypotheses on the role of iC3b- and C3d-binding
in the pathogenesis of candidiasis have been proposed.
"Bystander" deposition of complement fragments on
erythrocytes following activation of the alternate complement pathway by the fungus may promote fungal
rosetting of coated erythrocytes. This could provide fungal access to erythrocyte iron through candidal surface
hemolysin-mediated erythrocyte lysis (Manns et al.,
1994). Also, binding iC3b may mask the cells and prevent
phagocytosis, as discussed above.
Two major C3d-binding components have been identified, a 60-kDa moiety expressed on the surfaces of germ
tubes and a 50-kDa moiety in the yeast plasma membrane (Calderone et al., 1988; Linehan et al., 1988). In
other studies, antibodies to the major C3d-binding protein (60-kDa species) reacted with several components.
These molecules included a major 50- to 60-kDa moiety
and minor species of 94, 67-68, 60, 50, 40, 31, and 20 kDa
(Kanbe et al., 1991; Franzke et al., 1993; Lopez-Ribot et al.,
1995). The C3d receptor is expressed, in vivo, on organisms recovered from peritoneal lavage and in kidneys
from infected mice (Kanbe et al., 1991). A role for C3dbinding in pathogenesis is mostly speculative.
Hypotheses include: that aggregation of opsonized and
unopsonized cells could protect the fungus from phagocytosis; a role in iron acquisition, as suggested above for
iC3b binding; or binding to any host cell on which C3d
was deposited.
The ability of C. albicans to bind to the ECM ligands
fibronectin, laminin, entactin (nidogen), types I and IV
collagen, and vitronectin has been the focus of numerous studies in the last decade (for recent reviews, see
Fukazawa and Kagaya, 1997; Sturtevant and Calderone,
1997; Chaffin et al., 1998). Some of these ECM components are able to form complexes among themselves,
372
Grit
and, thus, ECM presents
host target with multiple
binding sites for the fungus. The identity of the adhesins
that recognize ECM components is unresolved and the

subject of some disagreement between studies.
Fibronectin is found in both plasma and ECM and was
one of the first host proteins identified as a ligand promoting C. albicans adherence (Skerl et al., 1984). Species of
62 kDa and 72 kDa have been isolated by affinity chromatography as adhesin candidates for fibronectin and
collagen (Klotz et al., 1993). The expression of fibronectinbinding capacity is regulated in part by environmental
conditions. Growth medium and temperature can alter
the extent of binding (Jakab et al., 1993; Negre et al., 1994).
Recently, growth in the presence of hemoglobin has been
reported to induce enhanced expression of a 55-kDa
promiscuous adhesin that recognized fibronectin,
laminin, and fibrinogen (Yan et aci., 1998a).
Glyceraldehyde-3-phosphate dehydrogenase, a 33-kDa
protein present predominantly on the yeast cell surface,
is also a fibronectin- and laminin-binding protein
(Gozalbo et al., 1998). Laminin adhesins of 68 kDa and 62
kDa have been identified by ligand affinity blotting
(Bouchara et al., 1990). These receptors may be the same
as the proteins binding to plastic (Tronchin et al., 1988)
and fibrinogen (Annaix et al., 1990) and, indeed, laminin
binding was reduced competitively by fibrinogen
(Bouchara et al., 1990). A 37-kDa receptor for laminin
that appeared not to recognize other ligands was first
detected with an antibody produced to a human highaffinity laminin receptor (Lopez-Ribot et al., 1994). Three
proteins (65 kDa,
and
44 kDa, 25 kDa) were detected, by ligaffinity blotting, as candidates for entactin binding
proteins (Lopez-Ribot and Chaffin, 1994). Binding of cell

wall protein to immobilized entactin was reduced by
fibronectin and laminin. Vitronectin appears to bind
both to cell wall protein (30-kDa moiety; Limper and
Standing, 1994) and to 13-glucan (Olson et al., 1996).
Fibronectin inhibited binding of vitronectin to the fungus
(Jakab et al., 1993).
Several studies have reported that peptides with the

acid) or related motif
were inhibitors of binding between fungal adhesins and
ECM components (Klotz et al., 1992; lakab et al., 1993;
Lopez-Ribot and Chaffin, 1994), while other studies have
suggested that the RGD motif is not a contributor to the
interactions (Negre et al., 1994; Yan et al., 1998b). Parallels
between fungal ECM binding proteins and mammalian
integrins that recognize ECM ligands and the RGD motif
raise the possibility of structural and antigenic relatedness. Antibody to the a531 mammalian integrin and
monoclonal antibodies to each subunit reacted with C.
albicans, and the reactivity increased as yeast cells formed
germ tubes (Santoni et al., 1994). Both high- and lowaffinity receptors have been detected, and the number of
RGD (arginine-glycine-aspartic
Med

10(3):359-383 (1999)
binding sites per C. albicans cell ranges from 5000 to

98,000 (Bouchara et al., 1990; Limper and Standing, 1994;
Negre et al., 1994). In vivo evidence for a role of adhesion
to fibronectin or any other ECM ligand in pathogenesis is
scant. In a rabbit model of infection, administration of an
RGD-containing peptide reduced fungal counts in several organs (Klotz et al., 1992). The promiscuity of adhesins,
the involvement of multiple adhesins in adherence, and
the presence of some host ligands, such as fibronectin,
in both superficial and deep sites suggest that there is
not a strict separation between the adhesins and mechanisms the fungus uses to colonize cutaneous and
mucocutaneous surfaces and that those that are
involved in deep tissue invasion.
nized individuals and the environment; underlying

immune suppression; and endogenous reservoirs for
reinfection. We have discussed the ease with which C.
albicans can enter the oral cavity and the central importance of immune suppression in the development of candidiasis. There can also be reservoirs for re-infection
within the oral cavity. C. albicans can be isolated from
plaque (Arendorf and Walker, 1980), oral biofilms (Kayla
and Ahearn, 1995; Hawser, 1996), and occluded acrylic
denture surfaces, where it will be relatively well-protected from topical antifungal agents but could be released
inadvertently by routine dental hygiene procedures and
lead to colonization of other oral sites.
(7) Clinical Significance of Colonization

and Its Prevention
Although C. albicans remains the most common cause of

nosocomial candidiasis, infections due to non-albicans
species are increasing (Pfaller, 1996). Some of these
species, namely, C. glabrata and C. krusei, are intrinsically
less sensitive to azole drugs. Another interesting trend is
(C) CANDIDA SPECIES AND DRUG RESISTANCE
(A) INCIDENCE OF CANDIDIASIS

The balance between colonization and mucosal candidiasis (Fig. 1) depends on the effectiveness of the host
defenses. A corollary of this is that candidiasis is often an
indication of an underlying immune deficiency. Oral candidiasis affects a large proportion of HIV-positive individuals and those with AIDS (Greenspan and Greenspan,
1996; Darouiche, 1998), and approximately 90% of AIDS
patients have suffered from oropharyngeal or esophageal
candidiasis at some stage of their illness (Alexander and
Perfect, 1997) Oropharyngeal candidiasis is also often
seen in the elderly, and merits investigation of potential
pre-disposing factors (Shay et al., 1997). A comprehensive
analysis of the literature concerning the treatment of
immunocompromised patients with oropharyngeal or
esophageal candidiasis indicates that optimal results are
achieved with the triazoles fluconazole and itraconazole
(Darouiche, 1998). They offer clinical efficacy at least comparable with that of the polyenes and imidazoles, together with a highly favorable mycological cure rate.
During the 1980s and 1990s, the frequency of nosocomial candidiasis has increased dramatically (Beck-Sague
and Jarvis, 1993; Pfaller, 1995, 1996). In a study of data
from the USA National Nosocomial Infections
Surveillance System, C. albicans was the most frequently
isolated fungal pathogen (59.7%) in hospital environments (Beck-Sague and Jarvis, 1993). Transfer of Candida
between individuals often occurs via the hands of health
care workers (Strausbaugh et al., 1994), and nosocomial
transmission can occur without candidiasis outbreaks
(Schmid et al., 1995a). This reinforces the need for appropriate cross-infection control in the dental surgery.
(B) RECURRENCE
A common feature of candidiasis is recurrence. Factors
which favor recurrence include: re-inoculation from colo10(3) 359 383 (1999)
10(3):359-383
the increased association of a novel Candida species, C.
dubliniensis, with oral infection in AIDS patients (Coleman et

al., 1997; Sullivan and Coleman, 1998). C. dubliniensis is
closely related to C. albicans (Coleman et al., 1997), and as
with C. albicans, stable fluconazole resistance can be
induced by exposure to the drug (Albertson et al., 1996;
Moran et al., 1997). Treatment of AIDS patients with prolonged courses of azole antifungal agents appears to have
selected for the development of azole-resistant C. albicans
strains (White, 1997a; Darouiche, 1998). Resistance can be
due to mutations in the drug target (White, 1997b;
Sanglard et al., 1998) or over-expression of drug efflux
pumps (Sanglard et al., 1995; Albertson et al., 1996). Overexpression of drug pumps from the ATP binding cassette
(ABC) family of efflux pump can lead to cross-resistance to
several azole antifungals (Albertson et al., 1996; Niimi et al.,
1997b). Most azole-resistant strains, however, retain sensitivity to amphotericin B (Albertson et al., 1996).
(D) PROSPECTS FOR STRATEGIES

TO PREVENT COLONIZATION
An attractive alternative to treating patients with candidiasis, which is often recurrent, is to prevent the infection from occurring. This could be achieved by increasing
the concentration of natural anti-candidal compounds in

the mouth or by preventing adherence. Denture resin has
been modified to enhance adsorption of the anti-candidal salivary protein histatin 5 (Edgerton et al., 1995).
Although adsorbed histatin 5 did not have an anti-candidal effect, desorbed histatin did, and modified denture
acrylic loaded with histatin 5 could provide a localized
controlled release of the protein. There is also the
prospect of using gene therapy to over-express histatins
in saliva (O'Connell et al., 1996).
Crit Rev
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Oral
Biol
Med
373
373
Another approach is the prevention of colonization

by inhibiting C. albicans adherence. This could be
achieved by immunizing the host or by physical interference with adherence mechanisms (Table 2).
Theoretically, the application of soluble receptors, ligands, or the domains of these molecules involved in
adherence could be used to prevent microbial colonization (Mandel, 1996). There is evidence that chitin is
involved in C. albicans adherence, and a chitin-soluble
extract (CSE) has been used to inhibit yeast adhesion to
a variety of cells (Segal, 1996). Although most adhesion
inhibition experiments have been carried out in vitro, initial in vivo results appear to be promising (Segal, 1996).
The oral environment is rich in proteinases, and any use
of peptides to inhibit adhesion may necessitate frequent
application. Other approaches to prevent microbial colonization include immunization (lenkinson and Lamont,
1997). Passive immunization with recombinant plant
monoclonal secretory antibodies to an S. mutans adhesin
has been used to inhibit specific microbial colonization
in humans (Ma et al., 1998). As significant adhesins in C.
albicans are identified, this approach could also be used
to preclude candidiasis. Salivary IgA antibodies have
been shown to reduce the adherence of C. albicans cells to
BECs (Epstein et al., 1982; Challacombe, 1994), and the
stimulation of a mucosal immune response with a C. albicans adhesin, possibly expressed by another resident oral
microbe, may prevent colonization.
The inhibition of S. mutans colonization is being considered for the prevention of caries (Ma et al., 1998), a
process which will make a significant, and possibly deleterious, change to the oral flora. C. albicans cells, however, are present in low numbers, and so removal is not
likely to have adverse effects on the remaining flora.
From this review, it is evident that C. albicans can utilize a
number of adherence mechanisms, and it is far from certain that inhibiting any one will prevent colonization. In
addition, C. albicans embedded in plaque may be protected from anti-adhesive compounds. However, the prophylactic treatment of susceptible individuals with these
compounds after aggressive dental hygiene might prevent the incorporation of C. albicans into plaque and the
development of a protected reservoir.
(8) Conclusion
C. albicans is truly an opportunistic organism. It is the
most frequent cause of candidiasis because it is the most
successful yeast at colonizing the oral cavity and so is
often in a position to take advantage of immune suppression in the host. C. albicans is the most adherent
Candida species, which is probably due to its ability to
adhere to many different ligands (Fig. 2b, Table 2). It possesses other virulence factors, such as the secretion of
hydrolytic enzymes and the ability to evade the immune
374
system, which give it a growth advantage over other

yeast. Subsets of these virulence factors may be activated by changes in the environment or contact with surfaces. In colonized individuals, however, C. albicans is usually present in the oral cavity only in relatively low numbers. This indicates that there is a fine balance between
colonization and clearance, and there is the prospect,
with further analysis of major adherence interactions, for
tipping this balance in favor of clearance.
Acknowledgments
RDC acknowledges financial support from the New Zealand Lotteries
Board and the University of Otago. WLC acknowledges support from
US Public Health Service grants A123416 and A140675. We are
grateful to Dr. Ann Holmes for helpful discussions.
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ORAL COLONIZATION BY CANDIDA ALBICANS

The presence of Candida albicans in the oral cavity is not

Candida species inhabit a variety of

and birds. In contrast,

days. The C. albicans strains were biotyped, and there was

tract is believed to be a major reserCole et

the oral cavity to the rectum and

Crit Rev Oral Biol Med

therefore, for the entry of Candida

nated food and drink.

(3) Maintaining an Oral

Crit Rev Oral Biol Med

Klotz and Smith, 1992; Gozalbo et al., 1998;

iC3b binding protein

Eigentler et al., 1989; Hostetter et al., 1990;

Fucose binding protein

Cameron and Douglqs, 1996

Enache et al., 1996

SAP (secreted aspartyl

Unknown (proteolytic modification

Watts et al., 1 998

ALS gene family

Imbert-Bernard et al., 1995

ular-weight yeast cell mannoproteins average more than

components, 3-1,3-glucan, 3-1,6-glucan, chitin, and

Adhesins are the fungal surface moieties that mediate

Crit Rev Oral Biol Med

corneum model, three isolates from oral infections

(C) ADHERENCE TO SKIN

such as diaper rash and intertriginous candidiasis.

(4) Adherence to Oral Surfaces

(A) ADHERENCE TO BECs

Crit Rev Oral Biol Med

The binding capacity of BECs from newborn full-term

to adherence in vivo for patients who are on courses of

Oral Biol Med

adhesin for a high copy number receptor (Staddon et al.,

fibronectin and iC3b adhesin(s) are described in more

gested that blood group antigens may act as epithelial

to BECs showed that proteins of 52-56 kDa differed in the

(B) ADHERENCE TO INERT POLYMERS

adherence may promote colonization and infection. C.

As dental prostheses are exposed to saliva and oral

acrylic but reduced adherence to BECs (McCourtie and

(C) ADHESION TO TEETH

growth conditions for the bacteria, however, can affect

(E) ADHERENCE TO SALIVA MOLECULES

with a salivary pellicle, it is reasonable to suppose that

Crit Rev Oral Biol Med

6 (O'Sullivan et al., 1997) and Psi (Newman et al., 1996),

(6) Evading Host Clearance Mechanisms

Crf Re Ora Bil Me

coated C. albicans by macrophage (Kolotila et al., 1987).

(A) FINDING BETTER ENVIRONMENTS

identified and may share identity with molecules

(B) ADHERENCE TO ECM AND SERUM PROTEINS

Protein-protein, lectin, hydrophobic,

CHOb (e.g., CSEC), peptide

leucine but not with other amino acids (Hawser and

(Bouali et al., 1987; Casanova et al., 1992; Martinez et al.,

Crit Rev Oral Biol Med

rescence flow cytometry, Gilmore et al. (1988) observed a

and, thus, ECM presents