1 Institute of Molecular Biosciences, Massey University, Private Bag 11 222, Palmerston North, New Zealand
2 Institute of Fundamental Sciences, Massey University, Private Bag 11 222, Palmerston North, New Zealand
Correspondence
Peter Farley
P.C.Farley{at}massey.ac.nz
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ABSTRACT |
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INTRODUCTION |
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The formation of germ tubes can be triggered by a variety of inducers, including serum (Odds, 1988). The induction of germ-tube formation by C. albicans in serum was first described by Reynolds & Braude (1956)
and was applied to the diagnosis of C. albicans infections soon after (Taschdjian et al., 1960
). Serum has been described as the magic potion for induction of germ-tube formation by C. albicans (Ernst, 2000
) because it is the most effective induction medium known (Gow, 1997
), but the active components have never been identified. It has been suggested that the lack of readily available nitrogen may be the trigger for germ-tube formation in serum (Gow, 1997
), but other reports have suggested that peptides (Barlow et al., 1974
), haemin (Casanova et al., 1997
),
-endorphin (Witkin & Kalo-Klein, 1991
) or hormones (White & Larsen, 1997
) may be the active component. Albumin is not the inducer because serum from a mutant rat lacking albumin can induce germ-tube formation while recombinant human albumin expressed and purified from Pichia pastoris can not (Feng et al., 1999
). Serum also triggers germ-tube formation in the yeast Yarrowia lipolytica (Perez-Campo & Dominguez, 2001
) and the emerging fungal pathogen Trichosporon beigelii (Walsh et al., 1994
).
In C. albicans, the major route for assimilation of ammonium is via the glutamine synthetase/glutamate synthase pathway (Holmes et al., 1991). Glutamine, which signals nitrogen repression (Marzluf, 1997
), can also be utilized as a sole nitrogen source (Limjindaporn et al., 2003
). Several lines of evidence suggest that germ-tube formation is not induced by nitrogen derepression. Not only do cells take up glutamine during glucose/glutamine-induced germ-tube formation (Sullivan et al., 1983
), but nitrogen derepression reportedly inhibits germ-tube formation (Holmes & Shepherd, 1987
). The MAP kinase signal transduction pathway, which has been implicated in signalling nitrogen limitation on solid medium, is not required for germ-tube formation on serum agar medium (Csank et al., 1998
). The transcription factor GAT1, which activates gene expression in response to nitrogen derepression, is not required for germ-tube formation (Limjindaporn et al., 2003
) and in particular, the gat1
mutant is unimpaired in its ability to form germ tubes in serum.
Germ-tube formation in C. albicans is triggered by several independent signal transduction pathways that respond to different environmental cues but the receptors that act upstream of these pathways are not known (Liu, 2001; Ernst, 2000
; Whiteway, 2000
). The environmental cues include pH, temperature and specific chemical inducers (Odds, 1988
). Serum induction of germ-tube formation may, therefore, result from signalling via more than one pathway. It has been possible, however, to characterize individual chemical inducers of germ-tube formation, for example N-acetylglucosamine (Cassone et al., 1985
), and therefore a reductionist approach was adopted in this present study to identify the chemical inducer present in serum.
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METHODS |
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Purification of the serum inducer of germ-tube formation.
Bovine serum (400 ml) was diluted to 20 % (v/v) with distilled water and fractionated on a Vivaflow 200 tangential-flow module (10 kDa cut-off membrane) set up for diafiltration. The retentate was recovered and stored at 20 °C. The permeant (5 l) (called F1) was applied, at a flow rate of 2 ml min1, to a DEAE-Sepharose column (5x53 cm, Pharmacia), that had been pre-equilibrated with 10 mM Tris/HCl buffer pH 9·0. The unbound fraction was collected, treated with Dowex SAX anion-exchange resin (40 g l1), filtered to remove the resin and lyophilized. The dry material was resuspended in one-hundredth the original volume of distilled water and filtered (0·2 µm). Trifluoroacetic acid (0·1 % w/v) was added and the sample was applied, in 1 ml aliquots at a flow rate of 1 ml min1, to a Jupiter C18 reverse-phase column (1x25 cm, Phenomenex) that had been pre-equilibrated with 0·1 % (w/v) trifluoroacetic acid. The absorbance of the column eluate was monitored at 230 nm and the leading unbound fraction from each run was collected and lyophilized. The dry material was dissolved in distilled water at a concentration of 50 mg ml1, treated sequentially with Dowex SCX cation-exchange resin (100 mg ml1) and Dowex SAX anion-exchange resin (100 mg ml1) and lyophilized. After each treatment with the ion-exchange resin the sample was filtered and centrifuged to remove the resin. The resin was washed with distilled water to recover entrapped inducer and the washes were added to the unbound fraction. The dry material was dissolved in one-tenth the original volume of 100 mM ammonium formate buffer pH 5·5 (nominally 500 mg ml1) and applied, in 0·1 ml aliquots at a flow rate of 0·5 ml min1, to a TSK G-Oligo PW column (0·78x30 cm, Phenomenex) that had been pre-equilibrated in the same buffer. The refractive index of the eluate was monitored and the leading peak was collected and lyophilized. The dry material was dissolved in the same buffer and reapplied, in 10-fold smaller aliquots, to the TSK G-Oligo PW column. The active peak (elution time 18 min) was collected, lyophilized, dissolved in buffer and reapplied to the column a third time to completely resolve the peak of active material (called F5) from the side fractions. Each time an eluate from the TSK G-Oligo PW column was lyophilized, the sample was dissolved in distilled water and lyophilized again, at least three times, to remove residual ammonium formate before further processing or assaying for activity.
Bioassay.
The bioassay was performed in microtitre plates (Brightman & Dumbreck, 1989). The assay contained: yeast cells (about 106 cells ml1), MgSO4 (1·20 mM), CaCl2 (0·04 mM), MnSO4 (0·014 mM) and the sample to be tested in a total volume of 103 µl. Assays in which glucose was the inducer also contained either 50 mM Bicine/NaOH buffer pH 8·0 or 50 mM potassium phosphate buffer pH 8·0 unless stated otherwise. The plates were covered with a plate sealer and incubated with shaking (250 r.p.m.) at 37 °C for 2 h. Germ-tube formation was assessed using an inverted microscope as described previously (Shepherd et al., 1980
). All assays were performed in duplicate. Immobilized
-D-glucose (Sigma) used in some experiments was linked to 4 % agarose beads via a 12 atom spacer. The pH of the serum used in this study was 8·5 and the concentration of glucose in this serum was 4·90±0·35 mM (n=22).
Glucose estimation and destruction.
Glucose was specifically removed from selected samples using glucose oxidase. Samples to be treated were first adjusted to about pH 7·0 and then incubated in 2·5 mM phosphate buffer pH 7·0 with 2 mg recombinant glucose oxidase (Roche) ml1 and 0·2 mg crystalline catalase (Roche) ml1 for 4 h at room temperature. Glucose concentrations were determined before and after this treatment by the hexokinase/dehydrogenase method essentially as described by Chaplin (1986).
NMR analysis.
All NMR experiments were performed at 25 °C with a Bruker Avance spectrometer operating at 400·13 MHz. The sample (approx. 0·4 mg F5) was dissolved in 0·5 ml D2O. Data were also collected for an equilibrium mixture of approximately 30 mg D-glucose in D2O.
Other methods.
Ammonium ion concentrations were determined using the indophenol reagent as described previously (Farley & Santosa, 2002). Ultra-clean water was prepared by distillation over charcoal. Statistical significance was determined using Student's t test (http://www.graphpad.com/quickcalcs/index.cfm).
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RESULTS |
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More than 80 % of the serum germ-tube-inducing activity was recovered in F1 (Fig. 2). Glucose oxidase treatment of F1 destroyed both the glucose (4·13±0·48 mM before and 0 mM after treatment) and the germ-tube-inducing ability of this fraction (80 % germ-tube formation pre-treatment compared to 0 % post-treatment, for the equivalent volume of F1). Glucose oxidase treatment of serum destroyed the glucose (0·00±0·01 mM after treatment, n=8) and made a statistically significant difference (P<0·05) to the percentage of germ tubes formed in the treated serum (68±16 %, n=3) compared to untreated serum (100±0 %, n=3).
Glucose-induced germ-tube formation
Germ-tube formation was induced by glucose over a slightly narrower range of pH than for serum (Fig. 4). At pH 8·0 the concentration of Bicine buffer had no significant effect in the range 550 mM (data not shown) but the level of germ-tube formation induced by glucose buffered with Bicine at pH 8·0 (69±7, n=11) was statistically significantly different (P<0·001) from that observed with glucose alone (7±10, n=11). Germ-tube formation was dependent on glucose concentration (Fig. 5
). The concentration of serum that gave 50 % germ-tube formation was 1·4 % (v/v); this corresponds to a glucose concentration of about 0·07 mM, which is similar to that required for 50 % germ-tube formation by buffered glucose (0·12 mM). C. albicans cells can be induced to form germ tubes in 0·5 % serum (33±26 %, n=15), which for bovine serum corresponds to a glucose concentration in the range 0·0130·025 mM (Knowles et al., 2000
; http://amvetlab.com/bovine.htm#chem; this study). This concentration of glucose is sufficient to trigger germ-tube formation (Fig. 5
). There was no statistically significant utilization of glucose during the time-course of the assay (5·19±0·14 mM compared with 5·67±0·39 mM in the control; P>0·05, n=4). No germ-tube formation was observed at 25 °C with either serum or buffered glucose over the time-course of the assay (2 h). Intriguingly, although high concentrations of glucose inhibited germ-tube formation in the buffered glucose assay, this was not observed when 10 % (v/v) serum was supplemented with additional glucose (data not shown). In 10 % (v/v) serum supplemented with additional glucose, no statistically significant utilization of glucose was observed (5·87±0·25 mM compared with 5·97±0·32 mM in the control; P>0·05, n=4). The length of germ tubes formed in buffered glucose (15·5±5·5 µm, n=40) was statistically significantly different (P<0·001) from those formed in serum (34·8±16·2 µm, n=40).
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Neither 0·5 mM 3-O-methyl glucopyranoside, 0·5 mM methyl--glucopyranoside, nor 0·5 mM methyl-
-glucopyranoside induced germ-tube formation under the conditions used, nor did these methylated sugars inhibit germ-tube formation induced by glucose (data not shown). Addition of 0·5 mM 6-deoxyglucose to the assay did not inhibit germ-tube induction by glucose nor did 6-deoxyglucose itself induce germ-tube formation (data not shown).
Induction of germ tubes by dialysed serum
Glucose accounts for most (>80 %), but not all, of the germ-tube-inducing activity in serum. Fractionation of serum by dialysis or filtration on a 10 kDa cut-off membrane removed the free glucose but produced a fraction (the dialysed serum or retentate) that contained a low level of an inducer of germ-tube formation (Fig. 2). Increasing the concentration of dialysed serum in the assay increased the level of germ-tube formation (Fig. 6
). However, whereas 50 % germ-tube formation was obtained with 1·4 % (v/v) serum (and a comparable concentration of glucose), this level of germ-tube formation required 14 % (v/v) dialysed serum. Induction of germ-tube formation by dialysed serum is due to a component of serum that is precipitable with trichloroacetic acid. After trichloroacetic acid precipitation of dialysed serum the supernatant (neutralized with NaOH) had lost its ability to induce germ tubes whereas the supernatant obtained after the same treatment of serum retained the ability to induce germ-tube formation. This was not due to the presence of an inhibitor in the supernatant from the dialysed serum because when 0·5 mM glucose was added to this supernatant, germ tubes were formed (60 % compared to 60 % for glucose alone and 0 % for the neutralized trichloroacetic acid supernatant alone). In addition, a solution of glucose treated with trichloroacetic acid in the same way as dialysed serum retained its ability to induce germ-tube formation (75 % germ-tube formation before and 70 % after treatment). It should be noted that the supernatant obtained by trichloroacetic acid precipitation of serum would contain free glucose. The pH optimum for germ-tube induction by dialysed serum was pH 8·5 (data not shown).
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DISCUSSION |
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Fractionation of serum by filtration or dialysis demonstrated that most of the germ-tube-inducing ability of serum could be attributed to a dialysable component(s). The inducer passed through a 1 kDa cut-off membrane (data not shown), as reported also by Feng et al. (1999), but a 10 kDa cut-off membrane was used to facilitate the processing of large volumes of serum. Subsequent fractionation of the filtrate by ion-exchange, reverse-phase and gel-filtration chromatography demonstrated that it contained a single active component that was identified as glucose. That the only active component in this fraction was glucose was then confirmed by the complete loss, in both the highly purified fraction (F5) and the crude filtrate (F1), of germ-tube-inducing activity following specific enzymic destruction of the glucose and by the demonstration that addition of glucose alone to dialysed serum was sufficient to restore germ-tube formation to a level indistinguishable from that obtained with serum.
Glucose has previously been reported to induce germ-tube formation in C. albicans (Hrmova & Drobnica, 1981; Vidotto et al., 1996
) and there have been reports of a link between candidiasis and both hyperglycaemia (Goswami et al., 2000
) and insulin-dependent diabetes mellitus (Guggenheimer et al., 2000
). Germ-tube formation in response to exogenous buffered glucose was observed in clinical isolates of C. albicans. Schmid et al. (1999)
identified a geographically widespread genotype that predominated amongst isolates from patients with candidiasis. Of the strains with this genotype tested, all but one formed germ tubes in response to glucose. The exception, strain CLB42, produced only a few (<5 %) germ tubes in serum. Of the other strains tested, all formed germ tubes in response to glucose. Although expression of a putative glucose transporter (orf19.3668) is up-regulated during germ-tube formation in serum (Nantel et al., 2002
), no significant glucose uptake was detected in this study and deletion of both copies of orf19.3668 did not prevent germ-tube formation in serum or buffered glucose (Q. L. Sciascia & P. C. Farley, unpublished).
Feng et al. (1999) implicated Ras1p-mediated signal transduction, via an adenylate cyclase pathway, as acting downstream of the dialysable serum inducer. The upstream receptor has not yet been identified but a glucose receptor is one possible candidate. In Saccharomyces cerevisiae, a glucose receptor, Gpr1p, located in the plasma membrane, is required for pseudohyphal growth (Palecek et al., 2002
). Activation of the downstream adenylate cyclase signal transduction pathway requires both a Gpr1p-mediated signal and an intracellular phosphorylated glucose signal (Rolland et al., 2000
). Two other glucose receptors are known in S. cerevisiae, Snf3p and Rgt2p, which have high and low affinity for glucose, respectively (Rolland et al., 2002
). Signalling by these receptors induces expression of different members of the glucose transporter gene family. A putative GPR1 orthologue (orf19.1944) and a large family of putative glucose transporters/receptors are present in the C. albicans genome (Fan et al., 2002
) but as yet only one member, a glucose transporter, has been functionally characterized (Varma et al., 2000
). Although a glucose sensor that is essential for germ-tube formation has yet to be identified, it seems unlikely that glucose is acting simply as a source of energy because (i) germ-tube formation can occur without significant uptake of the exogenous glucose, (ii) the expression of genes encoding glycolytic enzymes does not correlate with germ-tube formation (Swoboda et al., 1994
) and (iii) although C. albicans can grow on gluconolactone, glycerol or sorbitol, they can not be used in place of glucose to induce germ-tube formation.
A common protocol for induction of germ-tube formation by C. albicans is incubation of cells in YPD medium supplemented with 10 % serum (Lo et al., 1997). The serum contribution to the total glucose present in this medium (2 %, w/v) is insignificant and has no effect on germ-tube formation. Rather, it is a non-dialysable component of serum that induces germ-tube formation under these conditions. Serum is, therefore, the magic potion for the induction of germ-tube formation by C. albicans, not because of a lack of readily available nitrogen but because it is buffered at a slightly alkaline pH and contains two inducers that are both active at this pH, glucose and a non-dialysable component, the identity of which remains to be established.
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ACKNOWLEDGEMENTS |
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REFERENCES |
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Received 27 February 2004;
revised 18 May 2004;
accepted 2 June 2004.
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