Glucose Promotes Stress Resistance in the Fungal Pathogen \u3ci\u3eCandida albicans\u3c/i\u3e

Metabolic adaptation, and in particular the modulation of carbon assimilatory pathways during disease progression, is thought to contribute to the pathogenicity of Candida albicans. Therefore, we have examined the global impact of glucose upon the C. albicans transcriptome, testing the sensitivity of this pathogen to wide-ranging glucose levels (0.01, 0.1, and 1.0%). We show that, like Saccharomyces cerevisiae, C. albicans is exquisitely sensitive to glucose, regulating central metabolic genes even in response to 0.01% glucose. This indicates that glucose concentrations in the bloodstream (approximate range 0.05–0.1%) have a significant impact upon C. albicans gene regulation. However, in contrast to S. cerevisiae where glucose down-regulates stress responses, some stress genes were induced by glucose in C. albicans. This was reflected in elevated resistance to oxidative and cationic stresses and resistance to an azole antifungal agent. Cap1 and Hog1 probably mediate glucose-enhanced resistance to oxidative stress, but neither is essential for this effect. However, Hog1 is phosphorylated in response to glucose and is essential for glucose-enhanced resistance to cationic stress. The data suggest that, upon entering the bloodstream, C. albicans cells respond to glucose increasing their resistance to the oxidative and cationic stresses central to the armory of immunoprotective phagocytic cells

Glucose Promotes Stress Resistance in the Fungal Pathogen \u3ci\u3eCandida albicans\u3c/i\u3e

Metabolic adaptation, and in particular the modulation of carbon assimilatory pathways during disease progression, is thought to contribute to the pathogenicity of Candida albicans. Therefore, we have examined the global impact of glucose upon the C. albicans transcriptome, testing the sensitivity of this pathogen to wide-ranging glucose levels (0.01, 0.1, and 1.0%). We show that, like Saccharomyces cerevisiae, C. albicans is exquisitely sensitive to glucose, regulating central metabolic genes even in response to 0.01% glucose. This indicates that glucose concentrations in the bloodstream (approximate range 0.05–0.1%) have a significant impact upon C. albicans gene regulation. However, in contrast to S. cerevisiae where glucose down-regulates stress responses, some stress genes were induced by glucose in C. albicans. This was reflected in elevated resistance to oxidative and cationic stresses and resistance to an azole antifungal agent. Cap1 and Hog1 probably mediate glucose-enhanced resistance to oxidative stress, but neither is essential for this effect. However, Hog1 is phosphorylated in response to glucose and is essential for glucose-enhanced resistance to cationic stress. The data suggest that, upon entering the bloodstream, C. albicans cells respond to glucose increasing their resistance to the oxidative and cationic stresses central to the armory of immunoprotective phagocytic cells

Molecular analysis of a glycolytic gene and the effects of glucose on Candida albicans

The human fungal pathogen Candida albicans (C. albicans) shows considerable flexibility in adapting to environmental change.  C. albicans cells have evolved various defences, including specific stress responses, to evade the human immune system.  This study explored the relationship between central carbon metabolism and adaptational responses of C. albicans. The first aim was to assess the attractiveness of Fbal as an antifungal target.  C. albicans Fructose-1,6-bisphosphate aldolase (Fbal) is an essential metabolic enzyme required for both glycolysis and gluconeogenesis.  A conditional MET3-FBA1/fba1 mutant was used to assess the role that Fbal plays in the growth and virulence of C. albicans.  This revealed that Fbal enzyme levels must be reduced to less than 15% of wild type levels before the growth of this figures is inhibited.  Furthermore, Fbal depletion was shown to have a fungistatic, rather than a fungicidal effect upon C. albicans growth.  Also, the virulence of the MET3-FBA1/fba1 conditional mutant strain was only partially attenuated in the murine model of systemic candidiasis.  Hence, Fba1 is  not a particularly attractive antifungal target. The second aim was to study the effects of glucose on the C. albicans transcriptome, and to compare these with the corresponding glucose responses of S. cerevisiae.  C. albicans cells exhibited a subtly different transcriptional response to glucose compared with S. cerevisiae.  The responses of central metabolic genes to glucose were similar in these yeasts.  However, specific stress-responsive genes were up-regulated in C. albicans in response to glucose, and this was reflected in corresponding changes in stress resistance.  Thus, glucose responses are linked to certain stress responses in C. albicans.  This may contribute to the success of this fungus as a human pathogen.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effects of Depleting the Essential Central Metabolic Enzyme Fructose-1,6-Bisphosphate Aldolase on the Growth and Viability of Candida albicans: Implications for Antifungal Drug Target Discovery

The central metabolic enzyme fructose-1,6-bisphosphate aldolase (Fba1p) catalyzes a reversible reaction required for both glycolysis and gluconeogenesis. Fba1p is a potential antifungal target because it is essential in yeast and because fungal and human aldolases differ significantly. To test the validity of Fba1p as an antifungal target, we have examined the effects of depleting this enzyme in the major fungal pathogen Candida albicans. Using a methionine/cysteine-conditional mutant (MET3-FBA1/fba1), we have shown that Fba1p is required for the growth of C. albicans. However, Fba1p must be depleted to below 5% of wild-type levels before growth is blocked. Furthermore, Fba1p depletion exerts static rather than cidal effects upon C. albicans. Fba1p is a relatively abundant and stable protein in C. albicans, and hence, Fba1p levels decay relatively slowly following MET3-FBA1 shutoff. Taken together, our observations can account for our observation that the virulence of MET3-FBA1/fba1 cells is only partially attenuated in the mouse model of systemic candidiasis. We conclude that an antifungal drug directed against Fba1p would have to be potent to be effective

Glucose Promotes Stress Resistance in the Fungal Pathogen Candida albicans

Metabolic adaptation, and in particular the modulation of carbon assimilatory pathways during disease progression, is thought to contribute to the pathogenicity of Candida albicans. Therefore, we have examined the global impact of glucose upon the C. albicans transcriptome, testing the sensitivity of this pathogen to wide-ranging glucose levels (0.01, 0.1, and 1.0%). We show that, like Saccharomyces cerevisiae, C. albicans is exquisitely sensitive to glucose, regulating central metabolic genes even in response to 0.01% glucose. This indicates that glucose concentrations in the bloodstream (approximate range 0.05–0.1%) have a significant impact upon C. albicans gene regulation. However, in contrast to S. cerevisiae where glucose down-regulates stress responses, some stress genes were induced by glucose in C. albicans. This was reflected in elevated resistance to oxidative and cationic stresses and resistance to an azole antifungal agent. Cap1 and Hog1 probably mediate glucose-enhanced resistance to oxidative stress, but neither is essential for this effect. However, Hog1 is phosphorylated in response to glucose and is essential for glucose-enhanced resistance to cationic stress. The data suggest that, upon entering the bloodstream, C. albicans cells respond to glucose increasing their resistance to the oxidative and cationic stresses central to the armory of immunoprotective phagocytic cells