ORAL COLONIZATION BY CANDIDA ALBICANS
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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 mole-
cules, 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 contri-
bution of each mechanism to colonization.
Key words. Candida albicans, colonization, adherence, candidiasis.
(1) Introduction population studied. A compilation of data from a num-
ber of reports showed that the mean carriage rate for
The presence of Candida albicans in the oral cavity is not healthy individuals (no known underlying disease) was
indicative of disease. In many individuals, C. albicans is 17.7% (range, 1.9-62.3%), whereas mean carriage in hos-
a minor component of their oral flora, and they have no pitalized individuals (without clinical candidiasis) was
clinical symptoms. In certain sections of the population, 40.6% (range, 6.0-69.6%) (Odds, 1988). These data indi-
however, oral candidiasis occurs frequently and necessi- cate that the health of an individual is a predisposing
tates antifungal therapy. Oral presentations of candidia- factor for C. albicans colonization. A large number of sites
sis vary from the large white plaques of pseudomembra- in the oral cavity can be colonized; in healthy individuals,
neous candidiasis on the tongue and buccal mucosa to C. albicans is most commonly isolated from the mid-line
the palatal erythematous lesions of chronic atrophic can- of the middle and posterior thirds of the tongue, the
didiasis, and to angular cheilitis on the labial commis- cheek, or the palatal mucosa (Arendorf and Walker, 1979,
sures (Samaranayake, 1990; Scully et al., 1994; Shay et al., 1980; Borromeo et al., 1992).
1997). The primary etiological agent of oral candidiasis is It is of interest that only a proportion of the popula-
the yeast C. albicans; however, other species that cause tion is colonized by C. albicans, and only a subset of these
disease less commonly include C. tropicalis, C. glabrata, C. individuals develops candidiasis. Few longitudinal stud-
krusei, C parapsilosis, C. guilliermondii, and C. dubliniensis ies have been carried out on healthy individuals to see if
(Odds, 1988; Fridkin and Jarvis, 1996; Sullivan and Candida colonization is continuous. However, daily sam-
Coleman, 1998). Sequelae of mucosal colonization, par- pling has shown that C. albicans carriage persisted in a
ticularly of the gastrointestinal tract, may include pene- proportion of healthy people and that colonization
tration of the vascular system by Candida cells and recurred in a majority of the remaining subjects (Gergely
hematogenous dissemination (Cole et al., 1996). These and Uri, 1966; Williamson, 1972). In a study of 163
cells can then infect a variety of organs in immunocom- neonates in an intensive care and surgical unit, 21 of the
promised individuals and cause disseminated or sys- neonates initially carried C. albicans in their mouths, but
temic disease. only five yielded 6 or more yeast-positive cultures over
It is difficult to give a precise oral carriage rate for C. the 17-week study period (Sharp et al., 1992). These
albicans, since this depends on the age and health of the neonates were colonized for periods of between 7 and 63
1013)
10(3)-359-383 (1999)Crit
359 383 (1999) Crit Rev Oral Biol Med
Rev Oral
359
359
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.(2) Acquisition
Colonization Acquisition (a) Candida species inhabit a variety of
environments (Odds, 1988). C. albi-
b)
cans has been isolated
domesticated primates,
frommammals,
and other
GWt C. albicans Systemic marsupials, and birds. In contrast,
\ (d) Disease other Candida species have been iso-
\i' X lated from a much narrower range of
hosts (Odds, 1988). In humans, C.
Mucosl
Removal (c) diseases Oral
Oa cavity Ialbicans preferentially colonizes
mucosal surfaces, and the intestinal
tract is believed to be a major reser-
voir
al., for infection (Odds, can
C. albicans Cole et
1988;colonize
Figure 1. A model showing the interrelationship of factors involved in colonization of the oral 1996).
cavity by C. albicans: (a) acquisition, (b) growth, (c) removal, and (d) tissue damage and practically any site in the gastroin-
penetration. testinal 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).
days. The C. albicans strains were biotyped, and there was The vulvovaginal regions of approximately 40% of
unequivocal evidence for more than one infecting bio- healthy women are colonized by Candida species (Soll et
type in only 8.1% of colonized neonates. In immunocom- al., 1991), and the genito-urinary tract presents another
promised hosts, candidiasis is often caused by a resident reservoir for oral inoculation. C. albicans survives better
strain (Powderly et al., 1993; Voss et al., 1994), and the on moist surfaces than dry inanimate objects, but if the
same strain can cause recurrent infections (Miyasaki et degree of contamination is high enough, viable cells will
al., 1992). Some of the factors involved in the balance remain on dry surfaces for at least 24 hours (Rangel-
among clearance of C. albicans, colonization, and the Frausto et al., 1994). Many studies of nosocomial can-
development of candidiasis have been reviewed previ- didiasis in clinical settings have been carried out to
ously (Cannon et al., 1995a). The objective of this review determine how patients acquire infections (Hunter et al.,
is to focus on the initial, critical, step of colonization, 1990; Vazquez et al., 1993, 1998; Fridkin and Jarvis, 1996).
and to discuss the factors involved in colonization and It is evident that the most common means of transfer is
how current research might lead to therapeutic interven- contact with carriers, often the hands of hospital staff,
tions that could prevent colonization and, thus, preclude although various Candida species can be cultured from
candidiasis. inanimate objects (Hunter et al., 1990; Vazquez et al., 1993,
Colonization of the oral cavity by C. albicans can be 1998; Strausbaugh et al., 1994; Jarvis, 1996; Pfaller, 1996).
defined as the acquisition and maintenance of a stable A worrying finding in one of these studies was that C.
population of C. albicans cells which does not give rise to albicans could be cultured from the food given to two
clinical disease. A model based on this definition is patients in a bone marrow transplant unit (Vazquez et al.,
shown in Fig. 1. Colonization depends on the rate of 1993). Indeed, yeasts, including Candida species, are rela-
acquisition-that is, the rate at which yeast cells enter tively common contaminants of both processed and
the oral cavity-growth, and removal of cells from the unprocessed foods (Buck et al., 1977; Viljoen and
mouth by swallowing and oral hygiene. In a simplified Greyling, 1995). In a dental setting, the internal surfaces
model, if the rate of removal is greater than that of acqui- of dental unit water lines can become coated with bacte-
sition and growth, clearance will take place. If the rate of ria-rich biofilms (Tippett et al., 1988; Peters and McGaw,
removal is the same as that of acquisition and growth, 1996). Although there are no reports of yeasts being pres-
then there will be colonization. If the rate is lower and ent in these biofilms, this may reflect the culturing
there is tissue damage, it will lead to candidiasis. The methods used. If C. albicans were a component of such
presentation of candidiasis will depend on the tissue biofilms, contaminated water lines could constitute a
colonized, the virulence factors expressed by the Candida significant risk of inoculating oral cavities with yeast. In
cells, and the host response. So, colonization depends people whose mouths are colonized with C. albicans, the
on several factors: the acquisition or entry of cells into yeast can be found in saliva at an average concentration
the oral cavity, the attachment and growth of those cells, of 300 to 500 cells per mL (Arendorf and Walker, 1980).
the penetration of tissues, and the removal of cells from This will allow for transfer during kissing and other direct
the oral cavity. Each of these factors will be examined. saliva-saliva contact. There are ample opportunities,
360 ritRevOralBio Me lO3):39 33 (999
360 Crit Rev Oral Biol Med 10(3):359-383 (1999)
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.therefore, for the entry of Candida
species into the oral cavity by manual (a)
inoculation, saliva transfer, or contami-
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 con-
ditions 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 impor-
tance 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, 41i±49 3(1,3)-glucan, "`..i 13(1,6)-glucan, .L, mannoprotein, (&
faces. phosphodiester linkage, and 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 associat-
the 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 cer- However, a recent study reports that chitin measure-
tain growth conditions (Odds, 1988). The initial emer- ments 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 exten- microfibrillar 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 responsi- near 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 phosphopeptidoman-
the 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 cova-
lead 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 man-
Cassone, 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 manno-
is some quantitative variation. Chitin (an unbranched oligosaccharides. The N-glycosyl moieties of high-molec-
10(3) -359-383
1013) 359 383 (I1999)
999) Crit Rev Oral
Crit Rev Oral Biol Med 361
361
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C. albicans Adhesins and BEC Ligands
Adhesin Ligand Reference
Carbohydrate
Chitin Unknown Segal, 1996
Factor 6 oligomannosaccharide Unknown Miyakawa et al., 1992
Protein
66-kDa fimbrial protein Glycosphingolipid Yu et al., 1 994a
Fibronectin binding protein
(multiple candidates) 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 Fucose-containing oligosaccharide
(1 5-kDa fragment) (blood group antigen?) Cameron and Douglqs, 1996
GIcNAc or glucosamine Host oligosaccharide-containing
binding protein (190 kDa) GIcNAc or glucosamine Enache et al., 1996
SAP (secreted aspartyl Unknown (proteolytic modification
proteinase) of host or fungus?) Watts et al., 1 998
ALS gene family
ALSI Unknown Fu et al., 1998
ALA1 Unknown Gaur and Klotz, 1997
Other proteins (38-kDa, 54-kDa
candidate species) Unknown Imbert-Bernard et al., 1995
ular-weight yeast cell mannoproteins average more than components, 3-1,3-glucan, 3-1,6-glucan, chitin, and
600 mannose residues and those from germ tubes more mannoprotein (Kollar et al., 1997). The analysis of this
than 300 residues. In addition, single mannose residues material suggested that 3-1,6-glucan with some f-I,3-
and short, unbranched manno-oligosaccharides may be glucan branches may be linked to the reducing end of
0-linked to protein through serine and threonine. chitin. Covalent attachment of mannoprotein to 3-1,6-
Mannoproteins are found throughout the cell wall and glucan is through a remnant of the mannoprotein GPI
appear to be the dominant component at the cell sur- (glycosyl phosphatidyl inositol) anchor. However, each
face. Electron microscopic analysis shows a variable complex may not contain all four components, and the
number of cell wall layers (from 3 to 8) that seems to be proportion of cell wall polysaccharide involved in this
related to the technique used, the strain, and growth type of structure is unclear.
conditions of the fungus (Cassone et al., 1973; Rico et al.,
1991). This layering appears to be the result of quantita- (B) C. ALBICANS ADHESINS
tive differences in the individual components in different Adhesins are the fungal surface moieties that mediate
regions of the wall. Fimbriae, which may extend 110 to binding of C. albicans to other cells (host or microbial),
300 nm, radiate from the surface (Fig. 2a; Yu et al., 1994a). inert polymers, or proteins. Different experimental
The fimbrial subunit appears to be a highly glycosylated approaches and reagents have been used to identify C.
glycoprotein with an apparent molecular mass of 66 kDa albicans adhesins (also called binding proteins or recep-
(Yu et al., 1994a). tors) and host ligands (sometimes also called receptors).
The architecture of the yeast wall has been studied There is disagreement among some of these studies as
more extensively in Saccharomyces cerevisiae, and a number to the identity, number of candidal receptors for various
of observations suggest that the candidal cell wall will fit ligands, and the inhibitors of adherence (reviewed
the same model. In a recent study, material was isolated recently in Fukazawa and Kagaya, 1997; Sturtevant and
from a cell wall digest that contained all of the major wall Calderone, 1997; Chaffin et al., 1998). Our incomplete
362 Crit Rev Oral Biol Med 10(3):359-383 (1999)
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.understanding of the factors that influence the adher- corneum model, three isolates from oral infections
ence interactions is a likely source of apparently conflict- adhered more than a commensal isolate (Law et al., 1997).
ing observations. Following are examples of five factors Removal of lipid from the stratum corneum led to dou-
with the potential to affect observations: bling of the number of adhered organisms. Specific
(1) Some C. albicans strains are more adherent than epithelial lipids can modulate fungal adherence, since
others (Schmid et al., 1995b). binding was inhibited by fatty acids, sterols, and
(2) Some strains possess adhesins with different ceramides and was unaffected by squalene, steryl esters,
specificities (Critchley and Douglas, 1987a,b). cholesterol esters, and triglycerides. In a murine stratum
(3) In vitro growth conditions of the fungus-such as corneum model, yeast cells of C. albicans and C. stellatoidea
temperature (Lee and King, 1983), medium composition adhered in greater numbers than those of C. tropicalis,
(Alloush et al, 1996; Yan et al., 1998b), carbon source while C. guilliermondii, C. krusei, and C. parapsilosis cells
(McCourtie and Douglas, 1985; Gustafson et al., 1991), or showed little or no adherence (Ray and Payne, 1988). This
the presence of a specific inducer (Yan et al., 1998a)- hierarchy of adherence was similar to that observed with
may alter the expression of an adhesin. human epidermal corneocytes and BECs (Ray et al., 1984).
(4) Fungal cell viability may affect the extent of bind- In the murine stratum corneum model, the adherent cells
ing (Gorman et al., 1986). acquired fibrils and strands of an amorphous material
(5) The binding capacity of exfoliated human cells between the yeast and corneocyte cell surface, formed
used in adherence assays may differ among donors and cavitations at the site, and produced hyphae that invaded
from the same donor on different days (Sandin et al., corneocytes distal to the yeast attachment (Ray and
1987b) and with hormonal status (Theaker et al., 1993). Payne, 1988). Depletion of lipids had no effect on adher-
Despite differences between some studies, the gen- ence in this study, but pepstatin, an inhibitor of the fun-
eral conclusions are that C. albicans possesses multiple gal secreted aspartyl proteinase, inhibited the formations
adhesins and that there may be more than one adhesin of cavities around the adherent cells. Epidermolytic pro-
that recognizes a host ligand or cell. Most adhesins iden- teases, likely including the secreted aspartyl proteinase,
tified to date are mannoprotein, and, for individual have been isolated from strains recovered from patients
adhesins, both the protein and/or carbohydrate portions with cutaneous disease (El-Maghrabi et al., 1990).
have been implicated in adherence. Pepstatin, bovine brain gangliosides, and convalescent
(C) ADHERENCE TO SKIN human serum all reduced binding of yeast cells to cor-
neocytes. Although there may be differences among
Skin is a site of normal colonization as well as infections adhesins for corneocytes and BECs and vaginal epithelial
such as diaper rash and intertriginous candidiasis. cells (VECs), it is likely that there are at least some com-
Infections usually occur in individuals with some loss of mon adhesins. It appears, therefore, that C. albicans chitin
normal skin defenses such as abrasion and maceration, and proteinase may be important in skin colonization.
and yeast growth is promoted by a warm, moist environ-
ment (Samaranayake, 1990; Scully et al., 1994). Systemic (4) Adherence to Oral Surfaces
conditions such as diabetes, obesity, and various medical The oral cavity presents a number of surfaces for C. albi-
treatments may also contribute to susceptibility to skin cans adhesion. These include BECs, the inert polymers of
and other mucocutaneous infections (Odds, 1988; dental prostheses, teeth, and other oral micro-orga-
Samaranayake, 1990). C. albicans cells bind in vitro to cor- nisms. Adherence to each of these surfaces and the mod-
neocytes (keratinized cells of stratum corneum) from ulating effect of saliva on adhesion will be discussed.
individuals in these susceptible groups at twice the fre-
quency with which they bind to corneocytes from healthy (A) ADHERENCE TO BECs
individuals (Srebrnik and Segal, 1990). Amino sugars, Exfoliated BECs are probably the best-investigated
mannosamine, glucosamine, and galactosamine inhibit- human cell type in C. albicans adherence studies, and sev-
ed binding of C. albicans to human corneocytes and to eral adhesin/ligand interactions have been proposed
buccal epithelial cells (BECs) (Collins-Lech et al., 1984). A (Table 1). In interpreting the results of BEC adhesion
chitin-soluble extract (CSE) also inhibited binding of C. assays, one should note the following features: Fungal
albicans to human corneocytes (Kahana et al., 1988). C. albi- strain and source of epithelial cells affect adherence
cans cells exposed to nikkomycin, a chitin synthetase (Sandin et al., 1987b), the number of C. albicans cells that
inhibitor, had decreased chitin content and showed a cor- bind to individual BECs is variable (Sandin et al., 1987a),
responding decrease in adherence to BECs (Segal et al., there are both binding and non-binding BECs (Gorman et
1997). The site of adherence between the yeast cells and al., 1986; Polacheck et al., 1995), and both viable and non-
epithelial cells labeled intensely with wheat germ agglu- viable C. albicans cells bind to BECs, with the non-viable
tinin, a lectin-recognizing chitin. In a porcine stratum cells having a greater adherence (Gorman et al., 1986).
10(3) 359-383 (1999)
10(3)-.359-383 (1999) Crit Rev Oral Biol
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Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.The binding capacity of BECs from newborn full-term to adherence in vivo for patients who are on courses of
infants for Candida is less than that of BECs from prema- antifungal drugs.
ture infants, school-age children, and adults, but increas- The effect of treating BECs and/or C. albicans cells
es over the infants' first few days (Davidson et al., 1984; with antimicrobial agents on subsequent adherence has
Cox, 1986; Polacheck et al., 1995). Adherence was greater been studied extensively. The consensus of opinion is
to BECs from children with oral infection or colonization that treatment of BECs or yeast cells with any of a variety
than to BECs from uninfected controls but increased of agents-including chlorhexidine, hexetidine,
during a course of antibiotic therapy in previously unin- dequalinium chloride, cetrimide, cetylpyridinium chlo-
fected children (Cox, 1983). Menstrual cycle affects ride, octenidine, pirtenidine, taurolidine, propamidine
epithelial binding capacity, since BECs collected on day isethionate, noxythiolin, and aqueous garlic extract-
5 showed a binding capacity higher than that of cells col- reduced adherence (Gorman et al., 1986, 1987a,b; Tobgi et
lected on day 15, 22, or 28 (Theaker et al., 1993). In one al., 1987; Ghannoum, 1990; Ghannoum et al., 1990; Jones
study, VECs from the first and fourth weeks had a bind- and Fowler, 1994). Also, treatment of C. albicans with
ing capacity higher than that of VECs from the second or propamidine isethionate, octenidine, pirtenidine, and
third week (Segal et al., 1984), while another study sug- aqueous garlic extract reduced germ tube formation
gested that binding capacity peaked between the third (Jones and Fowler, 1994; Jones et al., 1997). Exposure to
and fourth weeks (Bibel et al., 1987). VECs collected from antifungal drugs may also reduce adherence to epithelial
pregnant or diabetic women also bound more C. albicans cells. Subinhibitory concentrations of amphotericin B,
cells than those from non-pregnant or non-diabetic con- nystatin, miconazole nitrate, and 5-fluorocytosine
trols, and 'infection isolates' adhered better than 'colo- reduced binding of C. albicans, C. tropicalis, and C. kefyr to
nizing isolates' (Segal et al., 1984). However, there was no BECs, and the effect of amphotericin B and 5-fluorocyto-
difference in the binding capacity of VECs from women sine combined was greater than that of either alone
with recurrent vaginitis compared with healthy controls (Abu-el Teen et al., 1990). A one-week course of flucona-
(Trumbore and Sobel, 1986). Palatal epithelial cells from zole also reduced the adherence of C. albicans to BECs
acrylic-denture-wearers with non-insulin-dependent dia- (Darwazeh et al., 1991). Drug treatment could be affecting
betes bound more fungal cells than did epithelial cells of cell-surface charge, or wall and membrane biosynthesis
non-diabetic individuals (Dorocka-Bobkowska et al., and structure.
1996). In another study, adherence to BECs from diabet- Binding of C. albicans to exfoliated epithelial cells is
ic individuals was similar to adherence to BECs from nor- affected by growth conditions of the fungus and can be
mal individuals (Polacheck et al., 1995). Thus, adherence inhibited by several reagents. Although there are some
to BECs is affected by many host factors, and hormonal differences among studies that may reflect the complex-
effects on adherence could be mediated by altering the ity of growth conditions and adhesin expression, there is
expression of adhesins on C. albicans cells or ligands on progress in characterizing the interactions and identify-
host cells. ing the fungal adhesins and host receptors. Growth of C.
There is also variability in binding to BECs from dif- albicans in media containing glucose, sucrose, galactose,
ferent donors (Sandin et al., 1987b). Adherence differed xylitol, or maltose enhanced binding to BECs and HeLa
when epithelial cells were collected on different dates, cells; maltose was the most effective and glucose the
but gender was not a factor. C. albicans adhered in greater least effective sugar (Samaranayake and MacFarlane,
numbers to BECs from AIDS patients than to BECs from 1982). Growth in the presence of glucocorticoids, dexa-
healthy individuals or transplant patients (Schwab et al., methasone, or triamcinolone acetonide also increased
1997). C. albicans isolates from patients in the early stages adherence to BECs (Ghannoum and Abu Elteen, 1987).
of AIDS adhered to BECs less well than did those from In one study, organisms grown at 250C were more adher-
healthy individuals. However, adherence of isolates ent than those grown at 37°C (Lee and King, 1983). Cell-
increased with the progression of AIDS until it exceeded surface hydrophobicity, which is increased at the lower
that of control isolates (Pereiro et al., 1997). Isolates from growth temperature, is suggested to contribute to, but
immunocompetent patients with esophageal candidiasis not be the predominant mechanism of, adherence to
adhered better than isolates from patients who were BECs (Hazen, 1989). A decrease in hydrophobicity may
heavily colonized but not symptomatic (Wellmer and contribute partially to the decrease in binding following
Bernhardt, 1997). Although there were differences among treatment of C. albicans with cetylpyridium chloride, tau-
strains, isolates from candidiasis patients were more rolidine, chlorhexidine acetate, or providone-iodine
adherent and formed germ tubes more rapidly than the (Jones et al., 1991, 1995). Another study demonstrated
other isolates. Analysis of these results is complicated by that an increase in temperature during growth promoted
the fact that the adherence of strains from AIDS patients adherence, and, as with growth on different carbon
has mostly been measured in vitro and may not correlate sources, this may be due to increased expression of an
364
(1999)
Grit
Crit Rev Oral Biol Med
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10(3):359-383
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Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.adhesin for a high copy number receptor (Staddon et al., fibronectin and iC3b adhesin(s) are described in more
1990). detail below.
Concanavalin A, a lectin-recognizing mannan, is an The secreted aspartyl proteinases (SAPs) also appear
inhibitor of adherence to BECs (Sandin and Rogers, to contribute to C. albicans adherence to BECs and other
1982; Sandin, 1987; Macura and Tondyra, 1989). Glucose, substrates (Ghannoum and Abu Elteen, 1986; El-
galactose, sucrose, or mannose enhanced adherence to Maghrabi et al., 1990; Watts et at., 1998). The SAP gene
BECs, while xylose, ribose, fructose, maltose, lactose, or family consists of at least seven members encoding 42-
raffinose had no effect on adherence (Macura and to 45-kDa aspartyl proteinases (Hube et al., 1994; Monod
Tondyra, 1989). Another study found no effect of galac- et al., 1994). The expression of proteinase isozymes
tose, N-acetylglucosamine (GIcNAc), ribose, or xylose depends on the strain, cellular morphology, and environ-
(Sandin, 1987). Thus, certain sugar residues may be mental factors (White and Agabian, 1995). Strains defi-
involved in a lectin-like adherence interaction or may cient in one or more of these genes have been con-
cross-bridge between adhesin and ligand. Lipids extract- structed. Deletions in SAPI, SAP2, or SAP3 reduced
ed from C. albicans or C. tropicalis inhibited binding to adherence of the organism to poly-L-lysine, an extracel-
BECs and involved individual phospholipids, sterols, lular matrix (ECM) preparation, or (slightly) to BECs
and steryl ester but not triacylglycerols or free fatty acids (Watts et al., 1998). However, a triple Asap 4-6 mutant
(Ghannoum et al., 1986). showed decreased adherence to the first two substrates
Several C. albicans cell wall proteins have been iden- but increased adherence to BECs. Pepstatin inhibited
tified as adhesin candidates for epithelial cells. In one binding of the parental strain to all three substrates. In
study, a yeast cell wall extract fractionated by con- addition to any direct effect on adhesion, proteinases
canavalin A-affinity chromatography followed by ion- may act on the yeast surface to modify adhesins or host
exchange chromatography yielded a fraction that sub- surfaces to expose ligands.
stantially inhibited yeast cell binding to BECs (Imbert- BEC glycosphingolipid is also an adherence target
Bernard et al, 1995). This fraction contained four moi- for C. atbicans. Several pathogenic yeasts, including C.
eties, of which the 38- and 54-kDa proteins were sug- albicans, bind to lactosylceramide ltGal( 1 -4)3Glc(l - )Cerl
gested as adhesins. 0-linked mannoproteins may also be (limenez-Lucho et al., 1990). C. albicans fimbriae bound to
involved in C. albicans adherence to epithelial cells. The C. BECs and reduced the binding of C. albicans yeast cells to
albicans CaMNTI gene encodes a mannosyl transferase BECs (Yu et al., 1994b). Purified fimbriae bind to an asialo-
involved in 0-linked mannosylation, and a Camntl null- GM, Igangliotetraosylceramide: 3Gal(1 -3)f3GalNAc( 1-
mutant showed reduced adherence to BECs (Buurman et 4)3Gal( l-4)f3Glc( 1-I )Cerl immobilized on microtiter
al., 1998). plates. The binding of fimbriae to BECs was inhibited up
Fibronectin was one of the first molecules to be sug- to 80% by asialo-GMP. Pseudomonas aeruginosa also binds
gested as a ligand recognized by a C. albicans adhesin to this glycosphingolipid through pili, and the adhesins
(Skerl et al, 1984). Both BECs and VECs stained with anti- from P. aeruginosa and C. albicans appear to share a com-
fibronectin antibody, and yeast cells pre-treated with mon binding domain (adhesintope) (Yu et al., 1994c,
fibronectin showed reduced binding to BECs and VECs 1996). Antibodies to this domain the aeruginosa pilus
in P.
compared with untreated cells (Skerl et al., 1984; Kalo et protein inhibit binding of both organisms to BECs, and a
al., 1988). The complement fragment iG3b has also been peptide derived from this region is also inhibitory.
implicated as a ligand involved in epithelial and The presence of candidal lectin-like epithelial
endothelial cell adherence (Gustafson et al., 1991; Bendel adhesins that recognize L-fucose or GlcNAc has been
and Hostetter, 1993; Bendel et al., 1995; also see reviews reported (Critchley and Douglas, 1987a,b). Fucose
by Hostetter, 1994; Chaffin et al., 1998). Glucose-grown inhibits binding of some strains to BECs, and glu-
cells express more iC3b receptor than glutamate-grown cosamine or GlcNAc inhibits the binding of other strains,
cells and show increased binding to human umbilical suggesting strain-specific receptors. Synthesis of the
vein cells (HUVCs) (Gustafson et al., 1991). Antibody to lectin-like material increased when organisms were
the human iC3b integrin receptor, iC3b, and several RGD grown on galactose (McCourtie and Douglas, 1985).
(arginine-glycine-aspartic acid)-containing peptides Extracellular material recognizing L-fucose inhibited
from iC3b reduced binding of C. albicans to HUVCs or binding of the homologous strain. Fucose has been
HeLa cells (Bendel and Hostetter, 1993). After growth of shown to bind to yeast and hyphal cells with approxi-
HeLa cells in serum-free medium, iC3b and fibronectin mately 2 x 107 binding sites per hyphal cell, mostly locat-
were detected on the cell surface, and treatment with ed adjacent to the hyphal tip (Vardar-Unlu et al., 1998). A
anti-C3 antibody, but not anti-fibronectin antibody, fragment of an L-fucose-binding protein was purified by
reduced adherence of C. albicans. although the reverse affinity chromatography with the blood group H trisac-
effect was observed with C. tropicalis. The candidates for charide antigen that terminates in fucose, and it was sug-
103 5 8 (9)Gi e rlBo e 365
10(3)-.359-383 (1999) Crit Rev Oral Biol Med
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.gested that blood group antigens may act as epithelial to BECs showed that proteins of 52-56 kDa differed in the
cell receptors for C. albicans (Cameron and Douglas, extract of attached yeast cells compared with those from
1996). The purified fragment inhibited binding to BECs unattached yeast or from BECs alone. Furthermore, anti-
by up to 80%. Binding to an esophageal cell line (Het-l) phosphotyrosine antibodies recognized 54-kDa and 60-
is partially mediated by a lectin-like interaction (Enache kDa species from the attached cells but not from cells in
et al., 1996). Yeast cells grown on galactose adhere better control cultures. These results suggest that contact of C.
than those grown on glucose, and GlcNAc or glu- albicans with a surface may activate signaling pathways
cosamine reduce binding by about 40%. A 190-kDa gly- that result in the expression of adhesins. Some C. albicans
coprotein detected in cell wall extracts of galactose- strains demonstrate the phenomenon of phenotypic
grown cells was postulated to be responsible for the switching (Soll, 1997). It is postulated that a 'master
increased adherence (Enache et al., 1996). switch' is responsible for turning off one set of genes and
The serotype A determinant, factor 6, of C. albicans switching on another set, some of which may be involved
mannan has also been implicated in epithelial adher- in virulence. It is possible that contact with a particular
ence (Miyakawa et al., 1992). A mutant strain deficient in surface activates a set of genes involved in adherence to,
the factor 6 determinant, or serotype B strains, showed and penetration of, that surface.
reduced adherence to BECs compared with non-mutant
serotype A strains. Mannan from the wild-type strain and (B) ADHERENCE TO INERT POLYMERS
anti-factor 6 antibody inhibited adherence to BECs. C. albicans adheres to a variety of materials found in med-
A genetic approach has yielded two candidate C. albi- ical devices, such as catheters and oral prostheses. This
cans adhesins for epithelial cells. The fact that S. cerevisiae adherence may promote colonization and infection. C.
cells adhere to a variety of surfaces significantly less well albicans is able to form biofilms on the surfaces of these
than do C. albicans cells has been used by several groups materials (reviewed in Chaffin et al., 1998). In addition,
to screen C. albicans genomic libraries for sequences that colonization may contribute to the deterioration of the
confer adherence on the non-adherent yeast. Separate devices (Marcuard et al., 1993; Gottlieb and Mobarhan,
screens have identified two members of a family of relat- 1994; Busscher et al., 1997; van Weissenbruch et al., 1997),
ed genes. Members of the C. albicans ALS (agglutinin-like and adherent organisms may be less susceptible to anti-
sequence) family are related to S. cerevisiae agglutinin fungal drugs (Kayla and Ahearn, 1995; Hawser, 1996).
genes that mediate cell-cell interactions during mating Most studies have focused on oral devices which may
of haploid cells (Hoyer et al., 1995). Als proteins have a contain multiple materials. Since these studies used dif-
central domain of a tandemly repeated motif that is rich ferent fungal growth conditions, different adherence
in serine, threonine, and proline. The sequence of ALSI assays, and different methods of analysis, the results
carries a signal for a GPI (glycosyl phosphatidyl inositol) cannot be compared directly.
anchor. Another member of the family, ALAl, was isolat- Hydrophobicity has been frequently, but not univer-
ed by the screening of a library for sequences that con- sally, implicated as a major factor in the adherence of
ferred adherence to ECM (Gaur and Klotz, 1997). Candida species to inert polymers. The more hydrophobic
Transformed yeast cells bound to fibronectin, laminin, species C. tropicalis, C. glabrata, and C. krusei adhered more
and collagen IV. In addition, adherence to BECs was to these polymers, including those found in denture
increased, suggesting that the adhesin may be multi- resin materials, than the less hydrophobic C. albicans, C.
functional, recognizing multiple ligands, and mediating stellatoidea, and C. parapsilosis (Klotz et al., 1985; Minagi et
adherence to different tissues. More recently, ALS1 has al., 1985, 1986; Miyake et al., 1986). Isolates of C. krusei, an
again been isolated in a screen of a C. albicans genomic emerging pathogen, showed variable but greater
library for sequences conferring increased adherence to hydrophobicity than C. atbicans isolates, and there was a
endothelial cells (Fu et at., 1998). Expression of ALS1 also correlation between hydrophobicity and adherence to
substantially increased binding of S. cerevisiae to the FaDu HeLa cells but not to denture acrylic (Samaranayake et
oropharyngeal epithelial cell line. More definitive evi- al., 1995). This suggests that factors other than
dence for the role of these proteins in candidal adher- hydrophobicity might contribute to the hierarchy of viru-
ence awaits further analysis in that organism. lence among Candida species. In an earlier study, isolates
Nonetheless, members of the Als protein family are cer- of C. albicans showed greater adherence to acrylic than
tainly candidates for adhesins that mediate adherence of isolates of other species (Segal et al., 1988). Adherence is
C. albicans in the oral cavity. increased on rough acrylic and silicone rubber surfaces
In addition to physical immobilization, adherence of compared with smooth surfaces (Verran and Maryan,
Candida cells to BECs may lead to alterations in fungal 1997). The acrylic base for dentures supported less
gene expression (Bailey et al., 1995). Analysis of proteins adherence of C. albicans than tissue conditioners and a
synthesized by C. albicans three hours following adhesion soft liner (Okita et al., 1991).
366 Crit
Crit Rev
Rev Oral
Oral Biol
Biol Med
Med
lO(3):359-383 (1999)
10(3):359-383 (1999)
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.As dental prostheses are exposed to saliva and oral acrylic but reduced adherence to BECs (McCourtie and
bacteria, a complex biofilm develops to which C. albicans Douglas, 1985). When germ tubes that adhered to poly-
cells can adhere. The fungus is present in biofilms in var- styrene were physically removed, several mannoproteins
ious morphological forms, and extracellular material were subsequently solubilized from the plastic (Tronchin
may also be present (Hawser and Douglas, 1994). The et al., 1988). Two major constituents of 60 and 68 kDa and
extent of biofilm formation is dependent on the nature of two minor constituents of high molecular mass (. 200
the inert material; the greatest biofilm formation was kDa) were obtained. While the relationship of the small-
found on latex, which is frequently used in urinary er species to similar-sized proteins described below as
catheters, followed by silicone elastomer and polyvinyl recognizing other ligands is unknown, the size similarity
chloride, often found in central venous catheters. has supported conjecture that there may be multi-func-
Formation of a biofilm was least on polyurethane and tional adhesins recognizing a variety of ligands. A 58-kDa
100% silicone. In vitro, gentle liquid flow increased the and a 37-kDa protein which bind fibrinogen and laminin,
formation of the extracellular matrix material, in which respectively, also bind to plastic and have been suggest-
the organism was embedded, compared with static con- ed to possess hydrophobic domains (Lopez-Ribot et al.,
ditions (Hawser et al., 1998). 1991, 1995). Among extracted cell wall proteins, there are
As with adhesion to BECs, treatment of either dental many that have hydrophobic domains. Analysis of pro-
acrylic or C. albicans cells with antimicrobial agents teins adsorbed to latex beads showed a spectrum of pro-
affects adhesion. Incubating acrylic with chlorhexidine teins in the 20- to 67-kDa range that may be more abun-
gluconate, amphotericin B, nystatin, but not a histidine dant in extracts from germ tubes (Lopez-Ribot et al.,
polypeptide, reduced binding to the polymer (McCourtie 1991). Hydrophobic interaction chromatography of
et al., 1985, 1986a,b; Spiechowicz et al., 1990). Exposure of extracted proteins suggested that the hydrophobic pro-
stationary-phase cells to chlorhexidine for a short peri- teins were usually smaller (< 50 kDa) than the
od, or growth of C. albicans in a sublethal concentration of hydrophilic proteins (> 90 kDa), perhaps reflecting the
chlorhexidine, reduced the adherence of the cells com- extent of glycosylation (Hazen and Hazen, 1992, 1993;
pared with unexposed cells, and the treated cells were Hazen and Glee, 1994). Hydrophilic cells exhibit a dense
more susceptible to the action of :3-glucanase. This sug- layer of fibrils not observed on hydrophobic cells, and it
gests an effect of chlorhexidine on the fungal cell wall. has been proposed that this layer masks the hydropho-
When C. albicans was grown in subinhibitory concentra- bic species. In keeping with this suggestion, the abun-
tions of antifungals, exposure to azalomycin F and dance of the acid-labile phosphodiester-linked manno-
aculeacin A increased subsequent adherence to acrylic, oligosaccharides was less in mannan from hydrophobic
while exposure to miconazole, ketoconazole, and cells than in that from hydrophilic cells (Masuoka and
amphotericin B did not alter adherence (Miyake et al., Hazen, 1997).
1990). Exposure to drugs did not change cell-surface
hydrophobicity, while the negative charge of the cell sur- (C) ADHESION TO TEETH
face decreased in the more adherent cells, suggesting The mouth is a unique part of the body in that it contains
that a decrease in electric repulsive force enhanced bind- exposed mineralized tissues, in the form of teeth. Beads
ing. Growth of C. albicans, C. krusei, C. kefyr, C. tropicalis, C. of crystalline hydroxyapatite (HA) have been used in
parapsilosis, and C. guilliermondii in subinhibitory concen- adhesion assays as a model for studying microbial adhe-
trations of sodium hypochlorite resulted in subsequent sion to tooth surfaces (Clark et al., 1978). C. albicans cells
reduction in adherence of all C. albicans strains and most do not bind well to hydrated HA beads, but adherence is
other species to polystyrene and BECs (Webb et al., stimulated greatly by pre-incubation of the beads with
1995). Growth in hypochlorite appeared to increase the either whole or parotid saliva ( Cannon et al., 1995b;
numbers and amounts of certain proteins in cell wall O'Sullivan et al., 1997). Adherence to saliva-coated
extracts from C. albicans and C. parapsilosis, again indicat- hydroxyapatite (SHA) beads is strain-specific (O'Sullivan
ing alterations in the cell wall composition. et al., 1997), and strains more frequently associated with
Several surface mannoproteins, among them candidiasis adhere significantly better to SHA beads
hydrophobic proteins, have been suggested as adhesin than do less pathogenic strains (Schmid et al., 1995b).
candidates for plastics (reviewed by Fukazawa and
Kagaya, 1997; Chaffin et al., 1998). Yeast cells grown in (D) CO-ADHERENCE
galactose were more adherent to acrylic than those C. albicans cells co-adhere with several species of oral
grown in medium containing glucose, sucrose, fructose, bacteria, including Streptococcus gordonii, S. mutans, S. oralis,
or maltose (McCourtie and Douglas, 1981). Material S. sanguis, S. salivarius, and Actinomyces species (Richards
found in the growth medium, when used to pre-treat and Russell, 1987; Branting et al., 1989; Jenkinson et al.,
acrylic or BECs, promoted adherence of C. albicans cells to 1990; Holmes et al., 1995b; Millsap et al., 1998). The
359383(199)
10(3 Cit Rv Orl Bd Me 36
10(3)-359-383 (1999) Crit Rev Oral Biot Med 367
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.growth conditions for the bacteria, however, can affect with a salivary pellicle, it is reasonable to suppose that
co-adherence (Richards and Russell, 1987; Millsap et al., microbial adherence interactions involve adsorbed saliva
1998), and some assays do not take into account the molecules. Saliva pellicles increase the adherence of C.
kinetics associated with the larger size of yeast cells albicans cells to HA beads (Cannon et al., 1995b), poly-
(Millsap et al., 1998). Colonizing acrylic with oral strepto- methylmethacrylate (Edgerton et al., 1993), and to S. gor-
cocci in the presence, but not in the absence, of sucrose donii cells (Holmes et al., 1995a) (Fig. 2b). Adherence of C.
enhanced binding of C. albicans (Richards and Russell, albicans was greater to dental acrylic coated with whole
1987; Branting et al., 1989). C. albicans bound in greater saliva than to uncoated acrylic, and a coating of parotid
numbers to acrylic pieces coated with S. sanguis, S. saliva stimulated adherence more than a coating of sub-
mutans, or S. sobrinus than to uncoated acrylic, but in this mandibular-sublingual saliva (Vasilas et al., 1992). In an
case, pre-incubation of the bacteria with sucrose to earlier study, however, adhesion to acrylic was reduced
induce synthesis of extracellular polymers did not by an 18-hour whole-saliva pellicle (Samaranayake et al.,
increase binding (Vasilas et al., 1992). Protein-protein and 1980). Also, coating of acrylic surfaces with whole saliva
lectin interactions have been proposed for the adhesive reduced the contact angle and decreased the binding of
interactions between Candida and bacteria, although hydrophobic Candida strains, while the adherence of
hydrophobic and electrostatic interactions may also take more hydrophilic C. albicans was unaffected (Miyake et al.,
part (Millsap et al., 1998). Both carbohydrate (Holmes et 1986). Adherence to two experimental silicone soft-lin-
al., 1995b) and protein molecules (Holmes et al., 1996) ing materials was less than to a commercial product or
that act as C. albicans receptors have been identified on the acrylic base, varied with the strains, and was reduced
the surface of S. gordonii. A carbohydrate containing when the materials were coated with saliva (Waters et al.,
rhamnose, glucose, GlcNAc, and galactose, isolated from 1997). In another study, however, coating soft liners with
the cell walls of S. gordonii cells, acted as a receptor for C. saliva or serum increased adherence of C. albicans and
albicans adherence in an in vitro assay (Holmes et al., biofilm formation, although the effect varied with the
1995b). Gene disruption experiments have shown that C. material and protein source (Nikawa et al., 1997). Coating
albicans adherence to bacteria is multifactorial, and inter- also increased firm colonization and hyphal invasion,
actions involving the S. gordonii cell-surface polypeptides although the plasticizer used affected cavitation.
CshA, CshB, SspA, and SspB contribute to co-adherence Incubating polymethylmethacrylate beads with sub-
(Holmes et al., 1996). The co-adherence of C. albicans with mandibular-sublingual saliva enhanced C. albicans bind-
oral bacteria is species-specific. Pre-treating BECs or den- ing compared with coating them with parotid saliva
ture acrylic with S. salivarius, Escherichia coli, or Porphyromonas (Edgerton et al., 1993). Binding was reduced by treatment
gingivalis reduced subsequent adherence of C. albicans cells of yeast cells with protease or glycosidase or incubation
(Nair and Samaranayake, 1996a,b). Also, in one report, a with mannose or galactose. Interestingly, C. albicans cells
biofilm of S. gordonii reduced adherence of most C. albicans do not detectably bind proteins from saliva in the fluid
strains and other species to polystyrene (Webb et al., phase, apart from small amounts of mucin MG 1 and MG2
1995). This would suggest that C. albicans recognizes spe- (Edgerton et al., 1993; Newman et al., 1996), which would
cific receptors on certain oral bacteria which are expressed explain why added saliva did not inhibit adherence of C.
under particular growth conditions. albicans to SHA beads (Cannon et al., 1995b). This indi-
cates that C. albicans may have specific adhesins that rec-
(E) ADHERENCE TO SALIVA MOLECULES ognize cryptitopes on saliva molecules that are exposed
In the oral cavity, proteins from saliva selectively adsorb when the molecules adsorb to surfaces (Fig. 2b). Such
to surfaces to form acquired pellicles. The acquired adhesins would promote colonization and prevent sali-
enamel pellicle has been particularly well-studied, and va-mediated aggregation and clearance from the oral
after two hours' formation it has been found to contain cavity.
immunoglobulins, mucin, at-amylase, cystatins, proline- In order to identify the saliva proteins to which C.
rich proteins, lysozyme, glucosyltransferases, albumin, albicans cells adhere, investigators have developed blot
fibrinogen, and serum components (Kraus et al., 1973; overlay assays (Newman et al., 1996; O'Sullivan et al.,
Rolla et al., 1983; Al-Hashimi and Levine, 1989; Jensen et 1997), in which saliva proteins are separated by SDS
al., 1992; Edgerton et al., 1996). The composition of the polyacrylamide gel electrophoresis, electroblotted onto
pellicle depends on the underlying surface (Edgerton et nitrocellulose membranes, and incubated with either
al., 1996) and the composition of the saliva (Jensen et al., radiolabeled (O'Sullivan et al., 1997) or fluorescently
1992; Edgerton et al., 1996). The intra-oral composition of labeled (Newman et al., 1996) yeast cells.
saliva varies (Sas and Dawes, 1997), and this affects the Autoradiography or photography, respectively, reveals
pellicles formed at different sites, and hence the pattern the protein bands to which the cells bind. These studies
of microbial colonization. Since all surfaces are coated have identified basic proline-rich proteins, including IB-
368
368~~~~~~~ ilMdl()3933(99
GrtRvOa ~ ~ ~ ~
Crit Rev Oral Biol Med 10(3):359-383 (1999)
Downloaded from cro.sagepub.com by guest on August 2, 2015 For personal use only. No other uses without permission.6 (O'Sullivan et al., 1997) and Psi (Newman et al., 1996), includes the production of immunoglobulins and, if tis-
as receptors for C. albicans adhesion. sues are penetrated, the involvement of macrophages
and polymorphonuclear leukocytes (Challacombe, 1994).
(5) Growth The major immunoglobulin in saliva is secretory IgA
In order to maintain Candida populations in the oral cav- (SIgA); serum immunoglobulins enter the saliva via the
ity, cells must grow and multiply at a rate at least equal gingival crevicular fluid, but are present at low concen-
to that of clearance. The growth rate of C. albicans in sali- trations. SIgA does not fix complement efficiently; its
va is too low to be measured accurately, due to carbon major role is the agglutination of micro-organisms,
source limitation (Samaranayake et al., 1986), which is which are then swallowed more easily. Anti-Candida SIgA
presumably caused by the large number of bacteria in can be detected in saliva, and its concentration is
saliva. Therefore, any metabolic activity that helps C. albi- increased in whole or parotid saliva from HIV-positive
cans acquire carbon or nitrogen will aid its growth and individuals, but reduced in AIDS patients, suggesting
survival in the oral cavity. C. albicans secretes aspartyl pro- that a compensatory response is overcome with progres-
teinases, which are believed to contribute to the orga- sive immunodeficiency (Challacombe and Sweet, 1997).
nism's virulence in several ways (Hoegl et al., 1996). C. albicans can be ingested by neutrophils and
Tissue destruction may aid fungal penetration, but this mononuclear phagocytic cells (for a review of interac-
process could also release peptides as a source of nitro- tions with macrophages, see Vazquez-Torres and Balish,
gen or carbon. The proteinase Sap2, for example, 1997). The interactions between these cells and C. albi-
degrades gastrointestinal mucin, and mucin can act as a cans appear to involve both opsonic and non-opsonic fac-
sole nitrogen source for C. albicans (Colina et al., 1996). In tors. Components from the classic and alternative com-
addition, C. albicans secretes the hydrolytic enzyme N- plement pathways can also enhance phagocytosis by
acetylglucosaminidase (also called hexosaminidase), macrophages and neutrophils (Solomkin et al., 1978;
which cleaves chitobiose, the dimer of GIcNAc, into two Marodi et al., 1991). C. albicans activates the alternate
molecules of GIcNAc (Sullivan et al., 1984; Niimi et al., pathway of complement, and both iC3b and C3d frag-
1997a). C. albicans can use GlcNAc as either a carbon or ments can bind to C. albicans (adhesins for these frag-
nitrogen source. N-acetylglucosaminidase activity is ments are discussed below). A candidal-protective mech-
shown by C. albicans and C. dubliniensis and to a lesser anism has been proposed in which fungal binding of
extent by C. tropicalis cells (Niimi and Cannon, unpub- iC3b blocks neutrophil CR3 recognition of iC3b and
lished observation), species found relatively frequently in phagocytosis of iC3b-coated C. albicans is reduced. Yeast
the oral cavity. It is tempting to speculate that a function cells coated with an anti-human CR3 antibody, that
of this enzyme may be to cleave terminal GIcNAc residues blocked the candidal binding protein, were phagocy-
from host glycoproteins, and that this scavenging activity tosed by neutrophils to a greater extent than uncoated
gives these Candida species a selective growth advantage. cells (Gilmore et al., 1988). The clumping of C. albicans
Competition with other oral micro-organisms for cells coated with C3 fragments has also been proposed
nutrients, such as glucose, affects the growth rate of as a candidal-protective effect, since these aggregates
Candida cells. It is recognized that antibiotic treatment, are too large to be phagocytosed (Heidenreich and
which reduces the number of oral bacteria, is a predis- Dierich, 1985). On the other hand, host protection is
posing factor for oral candidiasis (Samaranayake, 1990). postulated for the binding of serum vitronectin, since
Oral bacteria are present in most oral sites at concentra- Candida cells coated with vitronectin show enhanced
tions much higher than C. albicans, and so the Candida binding to macrophages and phagocytosis (Limper and
cells must compete with them for adhesion sites and Standing, 1994).
nutrients, and be exposed to bacterial toxins and by- Macrophage mannose receptors also mediate the
products. adherence of C. albicans (reviewed by Vazquez-Torres and
Balish, 1997). Binding of C. albicans to murine spleen and
(6) Evading Host Clearance Mechanisms lymph node tissue is primarily to macrophages (Kanbe et
A major factor influencing the balance among clearance, al., 1993). A (31,2-linked mannotetraose in the acid-labile
colonization, and candidiasis is the interaction between C. albicans mannan as well as an acid-stable structure
C albicans cells and the host defenses (Cannon et al., were identified as adhesins (Li and Cutler, 1993; Kanbe
1 995a). Immune system defects are a major risk factor for and Cutler, 1994). A monoclonal antibody to (1,2-linked
candidiasis. Innate defenses include the epithelial barri- oligomannosaccharide, but not a monoclonal antibody
er and anti-candidal compounds in saliva such as to the acid-stable mannan epitope, in the presence of
lysozyme (Tobgi et al., 1988), histatins (Xu et al., 1991), complement, enhanced phagocytosis of yeast cells by
lactoferrin (Nikawa et al., 1993), and calprotectin (Muller neutrophils (Caesar-TonThat and Cutler, 1997). Soluble
et al., 1993; Challacombe, 1994). Acquired immunity mannan can inhibit phagocytosis of complement-C3-
36
lO(3:3593831999 Crf Re Ora Bil Me
10(3):359-383 (1999) Crit Rev Oral Biot Med 369
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