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Infection and Immunity, September 2003, p. 4970-4976, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4970-4976.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Skin Facilitates Candida albicans Mating

Salil A. Lachke, Shawn R. Lockhart, Karla J. Daniels, and David R. Soll*

Department of Biological Sciences, The University of Iowa, Iowa City, Iowa 52242

Received 30 April 2003/ Returned for modification 5 June 2003/ Accepted 24 June 2003


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Mating between natural a/a and {alpha}/{alpha} strains of Candida albicans requires that cells first switch from the white to opaque phase phenotype. However, because cells expressing the opaque phase phenotype are induced to switch back to the white phase phenotype at physiological temperature (37°C) and because opaque phase cells are highly efficient at colonizing skin, we tested whether skin, which is several degrees lower than physiological temperature, is conducive to mating. Using a model in which a mixture of a/a and {alpha}/{alpha} cells are incubated for 24 h under a cotton patch on the hairless skin of newborn mice and using scanning electron microscopy to visualize cells on skin, it was demonstrated that skin facilitates mating. In some regions of the skin, 40% of all cells had fused. All of the stages of mating observed in vitro were observed in vivo. However, some unique morphological characteristics of mating on skin were observed and are attributable to parent cell immobilization on the skin. In control experiments on glass, plastic, and silicone elastomer surfaces at 32°C, cells either failed to fuse or did so at an extremely low frequency, suggesting that unique features of the skin surface other than reduced temperature also facilitate fusion.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Until recently, Candida albicans was believed to lack a sexual phase. This all changed when Hull and Johnson (7) identified the mating type locus (MTL). They found that one copy of the MTL locus contained a homolog to the Saccharomyces cerevisiae MATa1 gene, and the other copy contained homologs of the S. cerevisiae MAT{alpha}1 and MAT{alpha}2 genes. The majority of natural strains were subsequently demonstrated to be heterozygous for the MTL locus (11). However, when these strains underwent homozygosis at the mating type locus, they were still not competent to mate. They first had to undergo the white-opaque transition (12, 14). Low-frequency mating was first demonstrated in vivo (8) and in vitro (13) before it was known that switching to the opaque phase was necessary for mating. High-frequency mating was then demonstrated between engineered MTL-hemizygous opaque a/- and opaque {alpha}/- cells (14) and between natural opaque a/a and opaque {alpha}/{alpha} cells (12). The stages of C. albicans mating in vitro have recently been described and include pheromone-induced shmooing, chemotropism of conjugation tubes, fusion of conjugation tubes, nuclear division and migration, vacuole expansion, daughter cell formation, and septation (12).

For C. albicans to mate in nature, opaque phase cells of homozygous a/a and {alpha}/{alpha} strains must come in contact and fuse. Mating is probably best effected on a surface or in a clump of cells where immobilization facilitates chemotropism and conjugation tube fusion and in a location where mixed strain colonization is most likely. Moreover, because of the temperature sensitivity of the opaque phase phenotype, it seems unlikely that mating occurs efficiently at physiological temperature (i.e., within the human body). When the temperature of an opaque phase culture is raised from 25°C to >=37°C, opaque phase cells convert en masse to the white phase growth form after two cell doublings (16-18, 21). Hence mating, which requires that both the a/a and {alpha}/{alpha} strains are in the opaque phase, may be restricted to environments outside the human body. Therefore, it may be no coincidence that opaque phase cells are far more successful than white phase cells in colonizing skin (10). Since skin presents an environment (i) with a temperature below that of physiological temperature, (ii) that would be more prone to mixed strain colonization, and (iii) that would immobilize cells and hence facilitate the mating process, we examined whether mating occurred between natural a/a and {alpha}/{alpha} strains of C. albicans on the skin of newborn mice. We demonstrate that skin facilitates mating.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Strain maintenance and growth. The following strains and their MTL genotypes were used in the described mating experiments: WO-1 ({alpha}/{alpha}) (17), P137037 ({alpha}/{alpha}) (11), P137005 (a/a) (11), and P175063 (a/a) (11). Strains were maintained in 20% glycerol at -80°C. For experimental purposes, cells were plated on agar containing modified Lee's medium, an amino acid-containing, defined medium supplemented with zinc and arginine (4). When distinctions had to be made between white and opaque phase colonies, the agar was also supplemented with 5 µg of phloxine B per ml, which differentially stains opaque phase colonies red (3).

Mating in suspension. Cells from several 5-day colonies exhibiting the same homogeneous phenotype were coinoculated into a flask containing liquid modified Lee's medium and grown for 12 h at 25°C in suspension on a rotary shaker. Cells were then pelleted and resuspended in fresh liquid modified Lee's medium. Approximately 107 cells from an a/a strain and approximately 107 cells from an {alpha}/{alpha} strain were mixed in 1 ml of medium in a plastic 15-ml Falcon tube and incubated for 6 h. The tube was agitated in a rotational water bath shaker at 250 rpm.

Mating on skin. The cutaneous mouse model for the colonization of skin has been described previously in detail (10). In brief, 2- to 4-day-old newborns obtained from White Swiss/Webster ND-4 mice (Sprague-Dawley, Madison, Wis.) were employed. A 4-mm2 nonwoven sterile cotton patch (Kendall Co., Mansfield, Mass.) was saturated with 10 µl of Dulbecco's phosphate buffer (pH 7.1) containing 109 a/a and 109 {alpha}/{alpha} cells per ml. The patch was spread over the skin on the back of the newborn. It was then fixed in position with First Aid waterproof tape (Johnson and Johnson, Racine, Wis.). Animals were maintained in isolation. At the end of the 24-h experimental period, newborns were sacrificed by CO2 anesthetization, the patch was removed, and the skin under the patch was excised and processed for scanning electron microscopy (SEM). To obtain the temperature of the skin surface, an elastic thermometer probe was taped to the skin of a newborn mouse or the forearm of a human with First Aid waterproof tape and monitored for 5 min. The stabilized temperature was recorded.

Mating on synthetic surfaces. Cotton patches containing the same mixtures of a/a and {alpha}/{alpha} cells as those spread on skin were spread on synthetic surfaces and taped with First Aid waterproof adhesive tape. Surfaces included glass coverslips (Surgipath, Winnipeg, Manitoba, Canada), plastic coverslips (Nunc Inc., Naperville, Ill.), or silicone elastomer (Cardiovascular Instrument Corp., Wakefield, Mass.). The patched surfaces were then placed in a petri dish that contained a filter paper saturated with water and incubated in a water-jacketed incubator at 32°C for 24 h. At the end of the incubation period, the patches were removed and cells were observed on the respective surface under a 40x objective using bright-field microscopy.

SEM. Excised skin patches were attached to dental wax by insect pins and fixed in 2.5% (vol/vol) glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.2) at 4°C. The skin patch was then washed twice in buffer and postfixed in 1% osmium tetroxide in sodium cacodylate buffer for 1 h. Skin patches were washed in cacodylate buffer and distilled water and then dehydrated in graded concentrations of ethanol. Samples were placed in perforated Beem capsules and critically dried in an Emscope CPD 3000 (Emscope Laboratories, Ltd., Ashford, England). They were then mounted on aluminum stubs, sputter coated with gold palladium in an Emscope SC500 (Emscope Laboratories, Ltd.), and examined with a Hitachi S-4000 scanning electron microscope (Hitachi Corp., San Diego, Calif.). Animal studies were performed within the guidelines of the Animal Care and Review Committee at The University of Iowa.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mating in vitro. In the first description of the cell biology of mating in vitro of C. albicans (12), cells were imaged either by phase-contrast or fluorescence microscopy. Since cells colonizing skin are best imaged by SEM, we first used this method to recharacterize the mating process in vitro (i.e., in clumps of cells in suspension cultures). When opaque a/a cells (strain P137005) and opaque {alpha}/{alpha} cells (strain WO-1) were mixed and rotated in suspension in growth medium, they underwent mating in clumps (12). Cells first formed broad evaginations, a process referred to as shmooing. These evaginations then expanded into conjugation tubes (Fig. 1A and B). SEM revealed that while the surface of the parent cell bodies possessed pimples, the conjugation tubes formed by them were free of pimples (Fig. 1A and B), characteristics that could not be assessed through the original light microscopy analysis (12). Conjugation tubes were unconstricted at the parent cell-tube junction and were on average wider than hyphae formed by opaque phase cells (1). Conjugation tubes made contact with each other at their apices prior to fusion (Fig. 1C and D). We assume that specific apical associations were facilitated first by clumping in the incubation flasks, which served to immobilize juxtaposed cells of opposite mating type, and second by chemotropism and selective adhesion. When tubes fused, a distinct collar formed at the site of fusion (Fig. 1E and F), again a morphological characteristic that could not be assessed through the original light microscopy analysis (12). The collar formed on one side of the fusion line (Fig. 1E and F). As in the earlier stages of shmooing and conjugation tube growth, while the parent cells were pimpled the conjugation bridges were free of pimples (Fig. 1E and F). The resulting zygote then formed a daughter bud from the conjugation bridge (Fig. 1G and H). The bud always formed to one side of the fusion collar. That portion of the conjugation tube demarcated by the collar from which the daughter bud formed differentially expanded, apparently to accommodate bud growth (Fig. 1G and H). Therefore, upon bud formation, one side of the conjugation tube was wider than the other. The bud, like the conjugation bridge, was devoid of pimples. Similar mating stages were observed for in vitro crosses between opaque phase cells of strains P137005 (a/a) and P137035 ({alpha}/{alpha}) and between opaque phase cells of strains P175063 (a/a) and P137037 ({alpha}/{alpha}).



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  		FIG. 1. An SEM analysis of C. albicans mating in vitro (i.e., in suspension). A mixture of a/a (P137005) and {alpha}/{alpha} (WO-1) cells was incubated in suspension for 6 h. Cells were then fixed and examined on a glass surface. Note that while parent cells were pimpled, shmoos (A and B), conjugation tubes (C and D), conjugation bridges (E and F), and daughter cells (G and H) were devoid of pimples. Arrows in panels C and D point to tube association. Arrows in panels E through H point to the position of the collar. PC, parent cell; DC, daughter cell. Bars, 2 µm.

 
Mating on skin. When either opaque a/a (P137005) or opaque {alpha}/{alpha} (WO-1) cells were incubated for 24 or 48 h in buffer in a cotton patch on the skin of a newborn mouse, they readily colonized the skin (Fig. 2A through D or E through H, respectively). During incubation, although daughter buds were observed (Fig. 2B, E, F, and G), no shmoos, conjugation tubes, or fusants (zygotes) were observed among more than 1,000 opaque a/a cells and among 1,000 opaque {alpha}/{alpha} cells examined by SEM. In marked contrast, when mixed a/a x {alpha}/{alpha} cultures were incubated in buffer in a cotton patch on the skin of newborn mice, shmoos, conjugation tubes, and fusants abounded (Fig. 3). Because these phenotypes occurred only in mixed infections, we conclude that they represent the stages of mating on skin.



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  		FIG. 2. While a/a (P137005) cells alone and {alpha}/{alpha} (WO-1) cells alone colonize skin, they do not exhibit any of the mating morphologies. Bars, 2 µm.

 


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  		FIG. 3. Mating occurs on skin between a/a (P137005) and {alpha}/{alpha} (WO-1) cells. Arrows in panels E and F point to tube associations. Arrows in panels G, H, K, and L point to collars. T, conjugation tube; PC, parent cell; DC, daughter cell. Bars, 2 µm.

 
As in the mating process in vitro, the conjugation tubes that formed on skin were free of pimples (Fig. 3A and B). These tubes grew along the crevassed surfaces of skin, turning in response to road blocks in the surface topography and, presumably, to gradients of pheromone released from cells of the opposite mating type (Fig. 3C and D). In some cases, tubes of two cells grew towards one another, eventually making apical contact (Fig. 3E and F). In most cases, the contacts were blunt ended. Upon fusion, a distinct fusion collar formed at the fusion site (Fig. 3G and H). The collars were greater in diameter than the rest of the conjugation bridge. As in the case of the collars formed at sites of fusion in vitro, one side of the collar was usually wider than the other. On average, the collars that formed at the sites of fusion of short tubes on skin were wider than those that formed in cell clusters in suspension. In some instances, the conjugation bridges that formed on skin were quite long (Fig. 3I and J), much longer than any formed in suspension, suggesting that the tubes had traveled relatively long distances across the skin prior to fusion. Finally, fusants formed a daughter bud from the conjugation bridge (Fig. 3K). The daughter bud always formed to one side of the fusion collar (Fig. 3L), as was the case in vitro (Fig. 1G and H). Although the frequency of fusants was much higher on skin than in suspension cultures, the frequency of conjugation bridges with daughter buds was lower on skin than in suspension cultures. We attribute this difference to the composition of the supporting solutions. In suspension cultures growth medium was employed, while in patches buffer was employed.

High frequencies of fusion on skin. In suspension cultures we estimate that, on average, 5 to 10% of cells in a 50:50 mixture of a/a and {alpha}/{alpha} cells fuse (12). On skin, the average field of cells contained approximately 10% fusants, but a significant minority of fields contained as high as 50% fusants (Fig. 4). No morphological characteristic of the skin was deemed unique by SEM analysis in those fields with high levels of fusants.



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  		FIG. 4. Mating occurs at high frequency on skin. Arrows point to fusants in these low-magnification fields. Bars, 4 µm.

 
The temperature of baby mouse skin. In our rationale for testing fusion on skin, we argued that it provided a lower temperature than physiological temperature (37°C) and, therefore, would not suppress expression of opaque phase genes or induce mass conversion to the white phase (16-18, 21). To directly test this point, the temperature of baby mouse skin and human skin was measured by taping a small temperature probe to skin with First Aid waterproof adhesive tape. The temperature of human skin was 32°C and that of baby mouse skin was 31.5°C, well below physiological temperature (37°C).

Mating on glass, plastic, and silicone elastomer. To test whether any surface would facilitate fusion, opaque a/a and {alpha}/{alpha} cells were mixed and added to a patch and the patch was taped to the synthetic test surface, just as in the skin experiments. After 24 h, the patch was removed and analyzed for the proportions of opaque phase cells, shmoo morphologies, and fusants (zygotes). Only those fields were scored in which at least 1 cell out of the approximately 50 to 75 cells exhibited a shmoo morphology. The same requirement was applied to fields of mixed a/a and {alpha}/{alpha} cells applied to skin. While 39% of cells fused on skin, 0, 0, and 2% of cells fused on glass, plastic, and silicone elastomer, respectively (Table 1). While 34% of the remaining cells on skin formed shmoos, only 8 and 5% of cells on glass and plastic did so (Table 1). However, 30% of cells formed shmoos on silicone elastomer (Table 1). These results demonstrate that even with the increased humidity provided to the cultures on glass, plastic, and silicone elastomer, none supported fusion to the extent of skin.


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  		TABLE 1. A comparison of fusion between a/a and {alpha}/{alpha} cells on the surfaces of skin, glass, plastic, and silicone elastomer reveals that only skin facilitates fusion

 
Skin facilitates mating of all tested crosses. To be sure that the conclusion that skin facilitates mating of C. albicans could be generalized, we tested three crosses, P137005 (a/a) x WO-1 ({alpha}/{alpha}), the cross analyzed in detail above, P137005 (a/a) x P137037 ({alpha}/{alpha}), and P137063 (a/a) x P137037 ({alpha}/{alpha}). In all three cases, mating occurred at similar high frequencies after 24 h on skin (data not shown for latter two crosses). In all three cases, patches with up to 40% fusions were observed.


   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although genetic studies suggest that the population structure of C. albicans is primarily clonal, there have been indications in virtually every study of low levels of recombination (2, 5, 15). These indications were validated by the discovery of mating type-like genes (7) and the demonstration of mating in vivo (8) and in vitro (12, 13). C. albicans has one mating type locus (MTL), which in a majority of strains is heterozygous. Hence, to become MTL homozygous, C. albicans must lose one allelic copy, which contrasts with the cassette systems of S. cerevisiae (6) and Candida glabrata (22). Perhaps an even more intriguing aspect of C. albicans mating is the inclusion of the white-to-opaque switch in the mating process (12, 14). C. albicans must undergo homozygosis in order to switch to the opaque phase, and then it must switch to the opaque phase (3, 17-20) in order to mate (12, 14). This latter dependency presents unique constraints on the mating process, since the opaque phase phenotype is unstable at physiological temperature (37°C) (17). The basic phenotypic transition between the white and opaque phases occurs at frequencies around 1 in 1,000 at 25°C. However, if a relatively homogeneous opaque phase cell population is transferred to 37°C, opaque phase-specific genes are immediately deactivated, and after two cell divisions white phase-specific genes are activated and opaque phase daughter cells are formed en masse (16-18, 21). Opaque phase cells injected into a mouse through the tail vein convert after just 1 day postinjection to the white phase growth form, presumably as a result of the increase in temperature (9). Hence, it seems likely that mating occurs normally outside the human body, where temperatures are below 37°C, and thus can support the opaque phase phenotype. Based on this premise and the fact that opaque phase cells differentially colonize skin (10), we tested whether mating occurred on the skin of a newborn mouse. The temperature of this surface was measured as 31.5°C, well within the range that supports the opaque phase cell phenotype.

Since SEM was the most effective method for visualizing skin colonization (10), we first had to recharacterize the cell biology of mating in vitro using SEM. Our results were similar to those previously described using phase microscopy, laser scanning confocal microscopy, and 3D-DIAS reconstruction (12). However, SEM also revealed the surface morphology of cells, tubes, and daughter cells. In particular, it revealed that while parent cells possessed unique opaque phase pimples, conjugation tubes, conjugation bridges, and young daughter buds did not. SEM also revealed a collar around the conjugation bridge representing the point of tube fusion. These collars appeared to form on one side of the fusion line and, hence, may be specific to the bridge contribution of one mating type. SEM also revealed that daughter cells formed on one or the other side of the seam, never at the seam, and that the side of the bridge from which the daughter cell formed differentially expanded.

Our results revealed that mouse skin facilitated mating between opaque a/a and opaque {alpha}/{alpha} cells. All of the morphological stages in the mating process (12) observed in suspension cultures in nutrient medium were also observed on skin, including shmooing, conjugation tube growth, apical tube association, apical tube fusion, and daughter bud formation from the fusion bridge. There were, however, differences. First, on a crevassed skin surface, conjugation tubes exhibited more bends than tubes formed in vitro, obviously a result of navigating the complex surface. Second, the collars that formed at the fusion junctions of short tubes on skin were wider than those formed in a suspension. It seems likely that the increase in collar diameter may be due to the greater immobilization of parent cells on skin compared to in vitro. In contrast, collars on very long conjugation tubes were not unusually wide. Finally, some conjugation bridges achieved lengths not observed in vitro in the SEM study performed here or in a previous conventional microscopic study of the cell biology of mating (12), suggesting that skin provides a more stable environment for the genesis of pheromone gradients and chemotropism over long distances.

To test whether skin uniquely facilitated mating or whether it facilitated mating like any other substratum, we also measured the frequency of fusion at 32°C on glass, plastic, and silicone elastomer, a material similar to that of intravascular catheters. Our results indicate that these surfaces do not facilitate fusion and, hence, that skin is a unique facilitator of fusion. These results did, however, reveal that of the three synthetic surfaces, silicone elastomer was the only one that facilitated shmooing.

Our results, therefore, demonstrate that skin provides an environment specifically conducive to mating. Because of direct contact with the environment, it is a logical location for multiple strain colonization involving a/a and {alpha}/{alpha} strains. Since skin supports opaque phase cell colonization over white phase cell colonization (10), it may actually select opaque phase cells from the environment, which must be MTL homozygous and hence either a/a or {alpha}/{alpha}. Since it is conducive to opaque phase cell growth because of its adhesive characteristics and temperature, skin provides an optimum environment for mating, as demonstrated here. No doubt, other environments outside the human body, especially those that support biofilm formation, such as catheters, will also prove to be conducive to mating. Indeed, of the three synthetic surfaces tested, only silicone elastomer facilitated shmooing although it, like glass and plastic, did not support fusion. Our results do not exclude mating within the animal, which has been demonstrated to occur at low frequencies in a systemic mouse model (8). Since white a/a and white {alpha}/{alpha} cells presumably can form opaque phase cells at 37°C at frequencies of 10-3 that maintain the opaque phase phenotype for two subsequent cell divisions (18, 21), a short time window does exist for fusion at physiological temperature in the host. However, our results suggest that environments, like skin, which are below physiological temperature are far more conducive to C. albicans mating.


   ACKNOWLEDGMENTS
 
This research was supported by National Institutes of Health grant AI2392 to D.R.S. S.A.L. and K.J.D. were supported by the Developmental Studies Hybridoma Bank at Iowa.


   FOOTNOTES
 
* Corresponding author. Mailing address: 302 BBE, Department of Biological Sciences, The University of Iowa, Iowa City, IA 52242. Phone: (319) 335-1117. Fax: (319) 335-2772. E-mail: david-soll{at}uiowa.edu. Back

Editor: T. R. Kozel


   REFERENCES
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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Infection and Immunity, September 2003, p. 4970-4976, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4970-4976.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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