Abstract

Candida species are yeasts and within the oral

cavity, Candida albicans is the most frequently
isolated. There is clear evidence that C. albicans
adheres to oral surfaces including acrylic dentures
and mucosa. The mechanisms of attachment differ,
with candidal adhesion to inert surfaces under the
control of hydrophobic and electrostatic forces and
adhesion to mucosa dependent on a number of
complex ligand-recognition systems. Other factors
within the oral environment such as saliva, pH,
bacteria and hyphal formation have been shown to
influence adhesion of candida species to surfaces
in the mouth.
Key words: Candida albicans, adhesion, hyphae,
denture.
(Received for publication January 1997. Revised April
1997. Accepted April 1997.)
Introduction
In recent years there has been an increasing
interest in candidal infections in immunosuppressed
and otherwise medically compromised individuals.
This has resulted in a large volume of research data
which has focused attention on Candida albicans as
the primary aetiologic agent of candidosis, a disease
which can vary from superficial mucosal lesions to a
life-threatening systemic form. Oral candidosis in
the form of candida-associated denture stomatitis is
a common disease in some 65 per cent of denture
we a r e rs, and C. albicans, Candida glabrata a n d
Australian Dental Journal 1998;43:(1):45-50
C a n d i d a - a s s o c i ated denture stomat i t i s . Aetiology and
m a n a g e m e n t : A r e v i e w.
Pa r t 1. Fa c t o r s influencing distri bution of candida species in the oral cav i t y
B. C. Webb*
C. J. Thomas
M. D. P. Willcox
D. W. S. Harty*
K. W. Knox*
Candida tropicalis have been isolated from such
cases.
1
This review focuses on the ecology of candida
species in the mouth.
Factors influencing distribution of candida
species in the oral cavity
Yeast cells or blastospores are unicellular, eukaryo t i c
organisms which multiply by a specific process of
mitotic cell division known as budding. A nomen-
clature for the different morphological stages of
candida development has been clearly defined and
budding involves growth of new cellular material
from a particular site on the blastospore surface.
2
When the bud has grown to optimal size, nuclear
division occurs and a septum is formed between the
two cell units. A hypha has been defined as a micro-
scopic tube which contains multiple cell units
divided by septa and which may arise from existing
hyphae or from blastospores. The hyphae, which
develop from blastospores, are known as germ tubes
and they grow continuously by apical extension.
2
When blastospores are produced one from another
in linear fashion without separating, a structure
t e rmed pseudohypha is form e d .
3
True septat e
hyphae are produced by some candida species, such
as C. tropicalis, under certain circumstances, but true
hyphae are mainly associated with C. albicans. The
entire candidal cellular aggregate including hyphae,
branches and lateral buds is referred to as a
mycelium.
2
Macroscopic characteristics
Candida species form soft cream-coloured
colonies (Fig. 1) with a yeasty odour when grown
under aerobic conditions on medium which has a
Australian Dental Journal 1998;43:1. 45
*Institute of Dental Research, Sydney.
Faculty of Dentistry, The University of Sydney.
Cooperative Research Centre for Eye Research Technology, The
University of New South Wales.
Microscopic characteristics
The gross microscopic appearance of all the
species is similar; all yeasts are Gram-positive but
sometimes the shapes of the blastospores can vary
from ovoid to elongated or spheri c a l .
2
M i c r o s c o p i c a l l y,
C. albicans exhibits dimorphism (Fig. 2) in which
there is a transition from ovoid budding blastospores
( yeast cells) to parallel-sided hy p h a e .
2
Size also va ri e s ,
with measurements for C. albicans and C. krusei
blastospores being given as 2.9-7.22.9-14.4 m
and 2.2-5.64.3-15.2 m respectively.
2
The cells of
C. krusei appear elongated and have the appearance
of long grain rice, and Candida kefyr (Candida
pseudotropicalis) another clinically important species,
has a similar microscopic appearance.
4
Identification
The production of pseudohyphae is one of the
major differences between C. glabrata (a species that
cannot form pseudohyphae) and other medically
important candida species. Observation of germ
tubes and chlamydospores (large thick-walled cells
which develop at the tips of pseudohyphae) are also
helpful in identifying C. albicans.
3
All pathogenic candida species assimilate and
ferment glucose as a carbon source, none assimilates
nitrate as a nitrogen source, but they vary in their
abilities to utilize other carbon and nitrogen
s o u r c e s.
2
Carbon assimilation and occasionally
f e rm e n t ation studies are needed to differentiat e
candida species, for example, the clinically import a n t
candida species, Candida guilliermondii is the only
one to assimilate dulcitol and C. kefyr the only one
46 Australian Dental Journal 1998;43:1.
pH in the range of 2.5-7.5, and a temperature in the
range of 20-38C. Growth is usually detected in 48-
72 hours, and sub-cultures may grow more rapidly.
The ability of yeasts to grow at 37C is an important
characteristic to be considered in their identification
from clinical specimens as most pathogenic species
grow readily at 25C and 37C, whereas saprophytes
usually fail to grow at the higher temperature.
3
In
contrast to the convex colonies of other candida
species, Candida krusei grows as spreading colonies
with a matt or rough whitish yellow surface.
4
Fig. 1.Colonies of Candida albicans grown on Sabourauds medium
for 48 hours at 37C.
Fig. 2.Scanning electron micrograph showing dimorphism in Candida albicans grown on denture
acrylic for 48 hours at 37C; budding blastospores and hyphae forming mycelium are clearly
visible (bar=10 m).
to assimilate lactose.
3
Certain rare strains of C.
tropicalis may assimilate cellobiose weakly and show
an assimilation pattern similar to that of Candida
parapsilosis. The inclusion of arabinose is useful,
since C. parapsilosis readily assimilates this carbo-
hydrate whereas most strains of C. tropicalis do not.
3
The most frequently used yeast identification system
is the API 32 C and this utilizes the carbohydrate
assimilation tests described above.
Oral microbial ecology and distribution of
candida species
The opportunistic fungus C. albicans is the
commonest of the candida species found within the
oral cavity while other species which have been
isolated include C. glabrata, C. tropicalis, C. kefyr, C.
krusei and C. guilliermondii.
5
Candida organisms, as
commensal members of the normal oral microbiota,
are present on average in 40 per cent (20-60 per cent
range) of the human population.
5
The primary oral
source of C. albicans is considered to be the dorsum
of the tongue and other oral sites such as mucosa
and plaque-covered tooth surfaces are colonized
secondarily.
6
Candida species are also found as
harmless commensals of the digestive and vaginal
tracts. However, when the hosts defence system is
impaired, as in medically compromised and
immunosuppressed individuals, C. albicans infection
can lead to the establishment of candidosis, which is
manifested as superficial, involving the mucosa, or
disseminated, which is the more serious invasive
form.
7
Oral candidosis is one of the most common
fungal infections associated with HIV infection and
C. albicans is the species most often isolated, with C.
glabrata, C. tropicalis and C. krusei occasionally
detected.
8,9
C. kru s e i has been recently identified as an emergi n g
nosocomial pathogen because of its pathogenic and
clinical manifestations in hospitalized patients and
immunosuppressed and otherwise medically
compromised persons.
4
Specific factors affecting distribution of oral
candida
Saliva
Studies have shown that saliva reduces the adhesion
of C. albicans to acrylic whereas serum, which may
enter the oral cavity as a result of trauma to the
palatal mucosa, enhances adhesion.
10,11
In another
study it was suggested that it was the salivary
proteins or mucin that act as receptors for manno-
proteins on the surface of C. albicans.
12
This was
confirmed by the work of Edgerton et al.
13
and
Hoffman and Haidari s ,
1 4
who reported that C .
albicans selectively adsorbs salivary mucins and that
mucin-containing saliva enhances adhesion of yeast
cells to acrylic.
The reduction or complete absence of salivary
secretion in individuals with xerostomia due to
Sj ogrens syndrome (a group of symptoms including
enlargement of the parotid gland) has a profound
effect on the normal oral microbiota. The reduced
moisture level favours the growth of bacteria such as
Staphylococcus aureus, which is resistant to dryness,
and inhibits oral commensals adapted to high
moisture levels.
5
The study also showed that a low
salivary pH and a high oxygen tension alter the oral
e nvironment, and, as a result the numbers of
veillonella, commensal neisseria and micrococcus
species are reduced, while the growth of candida
species, Streptococcus mutans and lactobacillus
species is favoured.
pH
It has been suggested that an acidic environment
favours the colonization of candida species,
15
and
low pH levels have been observed in denture plaque
obtained from upper dentures of denture stomatitis
patients on sucrose or glucose-rich diets.
16
The effect of pH on the adhesion of C. albicans
strains to mucosal surfaces has been shown to vary
with the source of the mucosal cell and the strain.
17
A recent study by Verran et al.
18
has shown that C.
albicans strains appeared to behave differently in
response to a change of pH and that all strains were
capable of adhering to buccal epithelial cells (BEC)
at pH 7.3, 6.0 and 2.6, although adhesion was low.
However, adhesion to BEC was increased when
stationary phase cells were used instead of early
exponential phase cells, with one strain producing
hyphae at pH 2.6. In the same study pH did not
significantly influence adhesion to acrylic except in
one instance where the strain that adhered best did
so at pH 7.3, while two strains isolated from cases of
denture stomatitis produced hyphae at lower pH
values.
Adhesion
The interactions between C. albicans and the host
are complex, and several inve s t i g at o rs have suggested
that the mechanism of attachment involves inter-
actions between candida cell ligands and host cell
receptors.
19,20
The ligand receptors of C. albicans are
thought to be mannoproteins, and it has been
demonstrated that mammalian cell proteins iC3b,
fibrinogen, fibronectin and laminin will bind to C.
albicans as a result of candida CR3-like recognition.
20
C. albicans produces extra-cellular polymeri c
material which contains a mannoprotein adhesin.
The interaction between candida and epithelial cells
Australian Dental Journal 1998;43:1. 47
bioMerieux Vitek Inc., Hazelwood, Missouri, USA.
is thought to be one involving the protein portion of
the mannoprotein adhesin and the fucose or N-
acetylglucosamine-containing surface glycoproteins
of epithelial cells.
21
Recent inve s t i g ations indicate that the adhesion of
C. albicans to host cells is dependent on the type of
host cell and strain of the organism, and at least four
different candida-host cell recognition systems have
been descri b e d .
2 2 , 2 3
The first invo l ves blastoconidium
mannoprotein with lectin-like properties (mentioned
a b ove), which recognizes the terminal fucose or N-
acetylglucosamine-containing glycosides of host
epithelial cells. The second system invo l ves the
CR2/CR3 complement receptor of C. albicans, which
recognizes host endothelial cells. A 60 kDa manno-
protein extracted from hyphae appears to bind both
the amino acid sequence argi n i n e - g l y c i n e - a s p a rt i c
acid (RGD peptides) and non-RGD-containing
ligands; the RGD ligands are important constituents
of the extracellular mat rix of endothelial cells with
fibronectin being one of the proteins containing the
RGD sequence. Calderone
2 2
also mentions two other
systems which recognize receptors of epithelial cells,
n a m e l y, one involving a mannan oligosaccharide and
the other concerned with the chitin content of the
candida cell wall. It was suggested that the existence
of these ligand-recognition systems may explain the
wide range of sites susceptible to invasion by candida
species throughout the body.
2 2
O d d s
2 4
has indicated that the production of
v i rulence fa c t o rs in candida species may va ry
a c c o r d i n g to site, stage of invasion and nature of host
response. Most investigators agree that stationary
phase blastospores adhere better to tissue cells,
mucosal cells and acrylic than those at the exponential
(log) phase.
11,25,26
C. albicans undergoes a change,
producing an outer fibrillar-floccular layer from the
cell surface when it is grown to the stationary phase
in media containing high concentrations of specific
sugars. This material together with electrostatic
forces, is thought to be responsible for enhanced
candidal adhesion to acrylic in vitro. In the oral
cavity, colonization of the denture requires attach-
ment to the salivary pellicle (consisting of adsorbed
proteins and glycoproteins) covering the denture.
11
Mannoprotein (cell surface polysaccharide)
The cell wall of C. albicans is composed primarily
of the polysaccharides mannan, glucan and chitin.
The wall is of variable thickness and consists of
several layers with differing electron density. The
number of layers and their morphology varies and
this is related to such factors as stage of growth,
yeast form or germ tube, and growth medium but
usually there are five layers within the cell wall. The
outer fibrillar layer is composed of mannan or
mannoprotein which is also found in different locat i o n s
throughout the cell wall. Mannans represent about
40 per cent of the total cell wall polysaccharide or
15.2-22.9 per cent of the yeast cell wall (dry mass),
while -1, 3-D-glucans and -1, 6-D-glucans form
47-60 per cent by mass of the cell wall. Proteins,
lipids and chitin account for 6-25 per cent, 1-7 per
cent and 0.6-9 per cent by mass of the cell wall
respectively.
20
The role of mannoproteins as candida
cell wall adhesins has been discussed above.
Cell surface hydrophobicity (CSH)
Studies have shown that CSH is involved in the
adhesion of blastospores to human epithelial cells
and plastics. External cell wall protein changes in C.
albicans are thought to be responsible for changes in
hydrophobicity and hy d r o p h i l i c i t y.
2 7
The hy d r o p h o b i c
cells of C. albicans have been shown to bind diffusely
and plentifully to host tissues, whereas the hydro-
philic cells attachment is restricted to specific sites.
Hydrophilic cells bind to regions with macrophages
in contrast to hydrophobic cells which bind to tissue
areas free of macrophages,
28
earlier studies agreeing
with these findings.
29-31
This would indicate that
hydrophilic cells are more easily removed from the
body by phagocytosis than hydrophobic cells, which
can colonize epithelial surfaces. Hydrophobic inter-
actions which can operate over relat i vely long
separation distances could possibly facilitate specific
adhesin-receptor interactions, by bri n ging the
surfaces closer together.
28,32
It has been shown that the adhesion of candida
species to plastic surfaces is controlled by attractive
London-van der Waals forces (hydrophobic forces)
and electrostatic forces. The ability of candida
species to adhere to inert polymeric surfaces may
give the organisms direct access to the human host.
33
Oral bacteria
Bacteria may contribute to the colonization and
proliferation of candida strains in the oral cavity.
34
A
study has shown that the coaggregation of Strepto -
coccus sanguis, Streptococcus gordonii, Streptococcus
oralis and Streptococcus anginosus with C. albicans was
enhanced by subjecting the blastospores to glucose
starvation.
35
It was suggested that the coaggregations
involved protein-carbohydrate interactions, and it
was shown that heat or protease treatment of starved
candida cells eliminated their coaggregation with S.
sanguis and S. gordonii.
35
Another study demonstrated that C. albicans
would not readily adhere to acrylic that had not been
preincubated with streptococci, but did adhere to
the adherent S. sanguis and Streptococcus salivarius.
36
Branting et al. showed that adhesion of C. albicans to
acrylic surfaces was enhanced when the yeast was
incubated simultaneously with S. mutans.
37
48 Australian Dental Journal 1998;43:1.
Hyphae
There is agreement amongst most investigators
that the hyphal form of C. albicans is associated with
its invasiveness.
20,26,38
It has been demonstrated that
there is a strong correlation between germ tube
formation and increased adhesion of C. albicans to
BEC.
38
The study showed that germ tubes of C.
albicans exhibited enhanced adhesion to human
mucosal cells, which it was suggested, could be one
of the mechanisms related to virulence in candida
species.
38
It is thought that proteinases are produced
during hyphal formation which help to disrupt the
integrity of the oral mucosa.
39-41
A number of factors regulate the transition of C.
albicans from blastospores to hyphae. These include
temperature and pH of the growth medium, the
medium containing an inducer such as serum, N-
acetyl-D-glucosamine, L-proline, ethanol or a
mixture of amino acids, as in Lees medium and
va rious tissue culture media.
2 , 4 2 - 4 6
It has been
demonstrated in vitro that a temperature of 37-40C,
a pH of 6.5-7.0 and an initial blastospore
concentration not exceeding 10
6
/mL are essential for
growth of C. albicans hyphae within several hours.
2
The same study also showed that at temperatures
below 30C and pH less than 6.0 most C. albicans
strains on nutrient-poor media can form very long
hyphae over a period of several days.
2
Verran et al.
18
demonstrated that at pH 2.6, adherent C. albicans
were able to produce hyphae but suspended candida
cells did not have this ability.
A calcium-calmodulin interaction was shown to
induce blastospore-hyphae transition, whereas
u n r e s t ricted calcium uptake resulted in specific
inhibition of C. albicans hyphal growth
47,48
while
another study demonstrated that carbon dioxide
alone can induce germ tube form ation in C. albicans.
4 9
Holmes and Shepherd
5 0
found that exponential
phase blastospores of C. albicans formed germ tubes
after a period of glucose starvation followed by
transfer to glucose ammonium ion medium at 37C
and pH 6.5. It was shown that the presence of both
a carbohydrate and a nitrogen source was essential
for blastospore-hyphae transition.
Other studies have also demonstrated that the
nutritional status of the blastospore is an important
factor in regulating C. albicans morphogenesis.
51,52
Odds
2
considers that both morphological forms of
C. albicans, blastospore and hyphae, appear to
i n i t i ate and sustain pat h o l o gical responses in
mammalian hosts. However, it seems that one form
may be better adapted than the other to survive
under specific ecological conditions.
Enzymes
Studies of phospholipase A and lysophospholipase
activities have shown that C. albicans isolates that
adhered most strongly to BEC and were the most
pathogenic to mice, had the highest phospholipase
activities.
53
Some investigators have suggested that
hyphae produced by C. albicans m ay possess
phospholipase which allows entry to the host
epithelial cells
39
while Samaranayake
16
reported that
extracellular phospholipases and acid proteases of C.
albicans were activated by low pH conditions.
Proteinase has been shown to have an important
influence on candidal adhesion to and invasion of
oral epithelium.
40
In another study it was demon-
s t r ated that blastospores, after ingestion by
macrophages, quickly express proteinase which is
followed by increasing proteolytic activity with the
f o rm ation of germ tubes by the ingested blastospores
causing macrophage destruction.
54
This paper has reviewed data relating to factors
that influence the colonization of candida species
within the oral environment and candidal adhesion
to denture and mucosal surfaces. Part 2 of this
review will be concerned with oral diseases caused
by candida species.
Acknowledgements
This study was supported by a research grant
from the Faculty of Dentistry, University of Sydney.
The assistance of the Photographic Department,
Electron Microscopy Unit, University of Sydney is
gratefully acknowledged.
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Address for correspondence/reprints:
Dr B. C. Webb,
Institute of Dental Research,
2 Chalmers Street,
Surry Hills, New South Wales 2010.
50 Australian Dental Journal 1998;43:1.