Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
Correspondence
Geraldine Butler
Geraldine.Butler{at}ucd.ie
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ABSTRACT |
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INTRODUCTION |
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Formation of biofilms by organisms growing in association with a surface is a very common phenomenon among yeast and bacterial species (Hall-Stoodley et al., 2004; Jabra-Rizk et al., 2004
). In yeast, the most detailed descriptions of biofilm structure come from studies on Candida albicans (Baillie & Douglas, 1999
; Chandra et al., 2001
; Hawser & Douglas, 1994
; Kumamoto, 2002
; Shin et al., 2002
). In general, a layer of cells in the yeast form is found attached to the surface, with a layer of filamentous cells above, surrounded by an exopolymeric matrix (Kumamoto, 2002
). Cells in biofilms are associated with a specific gene-expression pattern, including the overexpression of amino acid biosynthetic genes, particularly those for amino acids containing sulfur (García-Sánchez et al., 2004
). Biofilm growth requires activation of the filamentation pathway and mutants defective in regulators of filamentation, such as efg1 and cph1, are unable to form biofilms (Ramage et al., 2002b
). C. parapsilosis is not capable of forming true filaments and biofilms are often composed of clumped blastospores (Kuhn et al., 2002
). Whilst it has been reported that C. parapsilosis biofilms are not as large as those generated by C. albicans (Kuhn et al., 2002
), this may be related to the growth conditions used; high-glucose media, in particular, greatly increase biofilm development by C. parapsilosis (Branchini et al., 1994
).
Bacteria form biofilms with somewhat similar structures to fungi. Cell attachment is also associated with changes in gene expression (Kuchma & O'Toole, 2000; Ren et al., 2004a
, b
; Schembri et al., 2003
; Schoolnik et al., 2001
). In some species, biofilm development is particularly associated with specific colony variants. In Pseudomonas aeruginosa, for example, a small-colony variant forms significantly more biofilm than other phenotypes (Häußler, 2004
). These variants consist of highly adhesive cells that are hyperpilated (Déziel et al., 2001
). The switch between phenotypic variants is regulated by a phase-variation mechanism involving the two-component response regulator PvrR (Drenkard & Ausubel, 2002
). In Vibrio cholerae, switching from a smooth to a rugose phenotype is also associated with increased biofilm formation and upregulation of genes involved in polysaccharide biosynthesis (Rashid et al., 2003
, 2004
; Yildiz et al., 2001
).
Switching between heritable colony phenotypes has been described in C. albicans (Slutsky et al., 1985; Soll et al., 1993
) and C. parapsilosis (Enger et al., 2001
; Lott et al., 1993
). In C. albicans, some phenotypes adhere differentially to mammalian cells (Vargas et al., 1994
). We therefore tested whether there is a correlation between phenotype and biofilm formation in C. parapsilosis. We show that one phenotype (called concentric), isolated readily from clinical isolates, forms quantitatively more biofilm and invades agar more readily than others. A second phenotype (smooth) forms less biofilm and does not invade agar to any measurable degree.
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METHODS |
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Microscopy.
To visualize cellular morphology of the four phenotypes exhibited by C. parapsilosis strain 74/046, cells of each colony phenotype were grown overnight in YPD medium. Aliquots (100 µl) of cells were washed twice in PBS and then resuspended in 100 µl calcofluor white solution (1 mg ml1) and 10 µl DAPI solution (4',6-diamidino-2-phenylindole; 1 mg ml1). Aliquots (5 µl) of the samples were then mounted on glass slides and cells were visualized and images were collected by using an F-View 2 digital camera from Soft Imaging Systems (SIS). The difference in width of pseudohyphae was calculated from measurements of 100 cells.
Biofilm formation.
Biofilms were generated essentially as described by Ramage et al. (2001). For assays using crystal violet, cells were grown to mid-exponential phase in YPD medium at 30 °C, 5x107 cells were washed twice in PBS and resuspended in 1 ml YPD medium containing 8 % glucose. Cell suspension (100 µl) was added to each well of a 96-well polystyrene plate and incubated at 37 °C (Kuhn et al., 2002
). The cells were allowed to adhere for 2 h and wells were washed twice with PBS to remove non-adhered cells; 100 µl fresh growth medium then was added to the wells and the plates were returned to the incubator for 48 h. To determine the effect of farnesol, cells were incubated in YPD medium containing 8 % glucose supplemented with 30 or 300 µM trans,trans-farnesol (Sigma). After 1260 h, the wells were washed twice with 200 µl PBS and biofilm mass was measured by using a crystal violet assay (Djordjevic et al., 2002
). Each of the washed wells was stained by adding 100 µl 0·1 % aqueous crystal violet solution and incubating at 30 °C for 15 min. The plate was then washed with sterile distilled water in an automated plate washer and destained with 100 µl 33 % (v/v) glacial acetic acid. After 4 h destaining, 100 µl H2O was added and 50 µl was then transferred to a new well. The amount of crystal violet stain in the destaining solution was measured spectrophotometrically (A570) (Stepanovic et al., 2004
). For comparison of isolates of C. parapsilosis, each assay was carried out by using two biologically independent samples measured in triplicate. For determining the effect of farnesol concentrations, six independent measurements were made. For microscopy, the wells were air-dried and images were captured with a light microscope (Zeiss Axiovert 200).
For dry-weight measurements, cells were counted by using a haemocytometer and resuspended at 5x107 cells ml1 in YPD medium containing 8 % glucose. Cell suspension (20 ml) was added to untreated Petri dishes (90 mm diameter) and allowed to adhere for 2 h. The plates were washed twice with PBS to remove non-adhered cells and reincubated in 20 ml fresh growth medium for 48 h. The biofilms were then washed three times in PBS and suspended in 10 ml PBS by using a cell scraper. The biofilms were collected on pre-dried and weighed cellulose filters (0·45 µm pore size, 47 mm diameter) and washed three times with water (10 ml). The filters were dried at 37 °C for 24 h and the dry weight of cells per filter was calculated. Dry weights were determined by using three independent cultures measured in triplicate (Hawser & Douglas, 1994).
Agar invasion.
Equal volumes of overnight cultures of each phenotype were spotted onto YPD agar plates and incubated at 30 °C for 96 h. The cells were photographed and those on the surface were removed by washing under running water. The cells remaining under the agar were then photographed.
Growth-kinetics determination.
Cell number was related to A600 readings by plating serial dilutions of exponential-phase cultures of the four switch phenotypes onto YPD agar. Growth curves were produced by inoculating 100 ml YPD medium with cells of each of the four switch phenotypes to give an approximate density of 7x104 cells ml1. A volume of 1 ml was then taken from each growing culture every 30 min and the A600 was measured. The readings over 24 h were then converted to cell number and represented graphically. Each assay was carried out with three independent cultures.
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RESULTS |
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The cell morphology of the four colony phenotypes also varies considerably (Fig. 2). Whilst the crepe and concentric phenotypes are mostly pseudohyphal, the cells of the concentric phenotype are approximately 45 % wider. Staining with calcofluor white (Fig. 2
) shows that chitin is distributed along the length of the cell, as well as at the bud neck, particularly in the concentric phenotype. Cells from the crater phenotype are elongated, but not pseudohyphal, and chitin is distributed around the cell wall and in the bud neck. Cells from the smooth phenotype are small and yeast-shaped, with chitin localized predominantly to the bud scars. These cells also have the smallest nuclei.
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The structure of the biofilms, as visualized by light microscopy, also varied with the phenotype (Fig. 3c). Cells from the concentric phenotype are entirely filamentous and cover the bottom of the polystyrene well. Cells from the smooth phenotype are small and yeast-shaped, and are distributed widely on the polystyrene surface with many gaps. Cells from the crepe and crater phenotypes are more elongated and form denser structures.
Phenotype affects invasion of agar
Several factors required for adhesion in C. albicans are also involved in invasion of tissue and other substrates (Dieterich et al., 2002; Fu et al., 1998
). The effect of phenotype on agar invasion in C. parapsilosis was determined by using isolate 74/046, which switches between all four phenotypes. Cells from each phenotype were grown in liquid culture to mid-exponential phase and equal volumes were inoculated onto solid YPD medium and incubated for 96 h. The colonies were photographed and then washed off the plate with running water (Fig. 4
). The mass remaining after washing is an indication of the amount of invasion of the agar. The concentric phenotype invades the most, leaving the greatest mass of cells after washing. The crepe and crater phenotypes also invade, although not to the same extent as concentric. Cells from the centre of the colony, in particular, are removed by washing (Fig. 4
). Cells from the smooth phenotype do not invade to any measurable extent. The invasion phenotypes therefore correlate well with the ability to generate biofilms.
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DISCUSSION |
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We have extended the observations of Lott et al. (1993) and Enger et al. (2001)
that phenotypic switching occurs in C. parapsilosis. We identify four core phenotypes, three of which are similar to those described by Enger et al. (2001)
. The fourth phenotype (crater) has not been described. Switching between all four phenotypes occurs at a high rate in three out of 20 C. parapsilosis isolates that were tested. The majority of isolates (13) switched between at least two different morphologies (Table 1
). We used a crystal violet assay to compare the ability of 14 isolates to generate biofilms and found that the concentric phenotype isolated from nine different strains formed the greatest amount of biofilm (Fig. 3
), whilst the smooth phenotype from eight strains formed the least biofilm. We also measured the dry weight of biofilm formed by the four phenotypes from three C. parapsilosis isolates. Both methods show that the concentric phenotype forms the most biofilm (from 1·75- to twofold higher), whilst the smooth phenotype forms the least.
In C. albicans, generation of biofilms is associated closely with the dimorphic switch from yeast to hyphal growth (Baillie & Douglas, 1999). Wild-type strains that are naturally defective in hyphal growth form only a thin basal yeast layer on catheter discs, whereas strains that grow only in filamentous forms generate dense biofilm mats (Baillie & Douglas, 1999
). In otherwise genetically identical strains, deleting efg1 and cph1, regulators of filamentation, abolishes or greatly reduces biofilm formation (García-Sánchez et al., 2004
; Lewis et al., 2002
; Ramage et al., 2002b
). C. parapsilosis strains do not form true hyphae (Odds, 1988
), but they do grow in pseudohyphal or other filamentous forms (Fig. 2
). The phenotype that grows only as small yeast cells on plastic (smooth) forms the least biofilm, whereas the phenotype that grows predominantly as a filament (concentric) forms the most biofilm. It is therefore likely that filamentation and biofilm formation in C. parapsilosis are also correlated closely.
The cell morphology of the four phenotypes when growing on plastic is similar, but not identical, to that of the cells growing in liquid culture (Figs 2 and 3). The concentric phenotype is filamentous under both conditions and the smooth phenotype grows only as yeast cells, whether on plastic or in liquid culture. The crater cells are also similar, forming elongated yeast cells. The crepe phenotype, however, is a mixture of pseudohyphae and elongated cells in liquid culture, yet grows only as elongated yeast cells when adhered to plastic. It is likely that adherence to plastic results in a major transcriptional change, affecting genes that are also involved in cell morphology.
Factors that regulate adherence to plastic and biofilm development in C. albicans are often also involved in cell adherence and invasion. The best characterized is Efg1, which, as well as being required for filamentation and biofilm development (García-Sánchez et al., 2004; Lewis et al., 2002
; Ramage et al., 2002b
), is also necessary for adherence and invasion of reconstructed human epithelia (Dieterich et al., 2002
). Members of the ALS adhesin family are also required for adhesion to human cells (Fu et al., 2002
; Zhao et al., 2004
) and are expressed differentially in biofilms (Chandra et al., 2001
). We used a very simple model to measure the ability of C. parapsilosis phenotypes to invade solid agar. The results correlated closely with biofilm development. The phenotype that is most filamentous (concentric) generates most biofilm and invades the agar to the greatest extent. Conversely, the phenotype growing only as small yeast cells (smooth) makes the least biofilm and does not invade agar. The smooth phenotype, however, grows more rapidly. It is therefore possible that C. parapsilosis exploits different environmental niches by undergoing phenotype switching. The smooth phenotype grows rapidly and so will be disseminated quickly. The concentric phenotype, however, is more efficient at adherence and invasion.
We do not yet understand the molecular mechanisms that regulate phenotypic switching and biofilm development in C. parapsilosis. However, we have shown that farnesol, a quorum-sensing agent in C. albicans (Hornby et al., 2001; Ramage et al., 2002a
; Shchepin et al., 2003
), also reduces biofilm formation by the crepe, concentric and crater phenotypes in C. parapsilosis. As in C. albicans, farnesol inhibits biofilm formation if added before allowing the cells to adhere, but has no effect following an adherence time of 2 h (Ramage et al., 2002a
). It is therefore likely that farnesol exerts its effect at early stages of biofilm development. Farnesol inhibits the filamentation pathway in C. albicans (Kruppa et al., 2004
; Sato et al., 2004
). C. parapsilosis does not generate true hyphae, but it does grow in a pseudohyphal form. The amount of biofilm generated by the highly pseudohyphal phenotype (concentric) is reduced most by farnesol, when added at 30 or 300 µM. However, farnesol has no effect on the morphology of the cells (data not shown). It is therefore likely that quorum sensing is also important for biofilm formation by C. parapsilosis.
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ACKNOWLEDGEMENTS |
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Received 29 October 2004;
revised 19 January 2005;
accepted 20 January 2005.
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