Sugar Sensing and Signaling in Candida albicans and Candida glabrata

Candida species, such as Candida albicans and Candida glabrata, cause infections at different host sites because they adapt their metabolism depending on the available nutrients. They are able to proliferate under both nutrient-rich and nutrient-poor conditions. This adaptation is what makes these fungi successful pathogens. For both species, sugars are very important nutrients and as the sugar level differs depending on the host niche, different sugar sensing systems must be present. Saccharomyces cerevisiae has been used as a model for the identification of these sugar sensing systems. One of the main carbon sources for yeast is glucose, for which three different pathways have been described. First, two transporter-like proteins, ScSnf3 and ScRgt2, sense glucose levels resulting in the induction of different hexose transporter genes. This situation is comparable in C. albicans and C. glabrata, where sensing of glucose by CaHgt4 and CgSnf3, respectively, also results in hexose transporter gene induction. The second glucose sensing mechanism in S. cerevisiae is via the G-protein coupled receptor ScGpr1, which causes the activation of the cAMP/PKA pathway, resulting in rapid adaptation to the presence of glucose. The main components of this glucose sensing system are also conserved in C. albicans and C. glabrata. However, it seems that the ligand(s) for CaGpr1 are not sugars but lactate and methionine. In C. glabrata, this pathway has not yet been investigated. Finally, the glucose repression pathway ensures repression of respiration and repression of the use of alternative carbon sources. This pathway is not well characterized in Candida species. It is important to note that, apart from glucose, other sugars and sugar-analogs, such as N-acetylglucosamine in the case of C. albicans, are also important carbon sources. In these fungal pathogens, sensing sugars is important for a number of virulence attributes, including adhesion, oxidative stress resistance, biofilm formation, morphogenesis, invasion, and antifungal drug tolerance. In this review, the sugar sensing and signaling mechanisms in these Candida species are compared to S. cerevisiae

Sugar Sensing and Signaling in Candida albicans and Candida glabrata

Candida species, such as Candida albicans and Candida glabrata, cause infections at different host sites because they adapt their metabolism depending on the available nutrients. They are able to proliferate under both nutrient-rich and nutrient-poor conditions. This adaptation is what makes these fungi successful pathogens. For both species, sugars are very important nutrients and as the sugar level differs depending on the host niche, different sugar sensing systems must be present. Saccharomyces cerevisiae has been used as a model for the identification of these sugar sensing systems. One of the main carbon sources for yeast is glucose, for which three different pathways have been described. First, two transporter-like proteins, ScSnf3 and ScRgt2, sense glucose levels resulting in the induction of different hexose transporter genes. This situation is comparable in C. albicans and C. glabrata, where sensing of glucose by CaHgt4 and CgSnf3, respectively, also results in hexose transporter gene induction. The second glucose sensing mechanism in S. cerevisiae is via the G-protein coupled receptor ScGpr1, which causes the activation of the cAMP/PKA pathway, resulting in rapid adaptation to the presence of glucose. The main components of this glucose sensing system are also conserved in C. albicans and C. glabrata. However, it seems that the ligand(s) for CaGpr1 are not sugars but lactate and methionine. In C. glabrata, this pathway has not yet been investigated. Finally, the glucose repression pathway ensures repression of respiration and repression of the use of alternative carbon sources. This pathway is not well characterized in Candida species. It is important to note that, apart from glucose, other sugars and sugar-analogs, such as N-acetylglucosamine in the case of C. albicans, are also important carbon sources. In these fungal pathogens, sensing sugars is important for a number of virulence attributes, including adhesion, oxidative stress resistance, biofilm formation, morphogenesis, invasion, and antifungal drug tolerance. In this review, the sugar sensing and signaling mechanisms in these Candida species are compared to S. cerevisiae.status: publishe

The Cdc25 and Ras1 Proteins of Candida albicans Influence Epithelial Toxicity in a Niche-Specific Way

The PKA pathway is a signaling pathway involved in virulence in Candida albicans. This mechanism can be activated via addition of glucose and activation involves at least two proteins, namely Cdc25 and Ras1. Both proteins are involved in specific virulence traits. However, it is not clear if Cdc25 and Ras1 also affect virulence independently of PKA. C. albicans holds a second, atypical, Ras protein, Ras2, but its function in PKA activation is still unclear. We investigated the role of Cdc25, Ras1, and Ras2 for different in vitro and ex vivo virulence characteristics. We show that deletion of CDC25 and RAS1 result in less toxicity towards oral epithelial cells, while deletion of RAS2 has no effect. However, toxicity towards cervical cells increases in both the ras2 and the cdc25 mutants while it decreases in a ras1 mutant compared to the WT. Toxicity assays using mutants of the transcription factors downstream of the PKA pathway (Efg1) or the MAPK pathway (Cph1) show that the ras1 mutant shows similar phenotypes as the efg1 mutant, whereas the ras2 mutant shows similar phenotypes as the cph1 mutant. These data show niche-specific roles for different upstream components in regulating virulence through both signal transduction pathways

Sugar Phosphorylation Controls Carbon Source Utilization and Virulence ofCandida albicans

Candida albicans is an opportunistic human fungal pathogen that relies upon different virulence traits, including morphogenesis, invasion, biofilm formation, and nutrient acquisition from host sources as well as metabolic adaptations during host invasion. In this study, we show how sugar kinases at the start of glycolysis modulate virulence of C. albicans. Sequence comparison with Saccharomyces cerevisiae identified four enzymes (Hxk1, Hxk2, Glk1, and Glk4) in C. albicans with putative roles in sugar phosphorylation. Hxk2, Glk1, and Glk4 demonstrate a critical role in glucose metabolism, while Hxk2 is the only kinase important for fructose metabolism. Additionally, we show that Hxk1 controls HXK2, GLK1, and GLK4 expression in the presence of fermentable as well as non-fermentable carbon sources, thereby indirectly controlling glycolysis. Moreover, these sugar kinases are important during virulence. Disabling the glycolytic pathway reduces adhesion capacity, while deletion of HXK1 decreases biofilm formation. Finally, we demonstrate that hxk2Δ/Δ glk1Δ/Δ glk4Δ/Δ and hxk1Δ/Δ hxk2Δ/Δ glk1Δ/Δ glk4Δ/Δ have attenuated virulence upon systemic infections in mice. These results indicate a regulatory role for Hxk1 during sugar phosphorylation. Furthermore, these kinases are essential during growth on glucose or fructose, and C. albicans relies on a functional glycolytic pathway for maximal virulence.status: publishe

The involvement of the Candida glabrata trehalase enzymes in stress resistance and gut colonization

Candida glabrata is an opportunistic human fungal pathogen and is frequently present in the human microbiome. It has a high relative resistance to environmental stresses and several antifungal drugs. An important component involved in microbial stress tolerance is trehalose. In this work, we characterized the three C. glabrata trehalase enzymes Ath1, Nth1 and Nth2. Single, double and triple deletion strains were constructed and characterized both in vitro and in vivo to determine the role of these enzymes in virulence. Ath1 was found to be located in the periplasm and was essential for growth on trehalose as sole carbon source, while Nth1 on the other hand was important for oxidative stress resistance, an observation which was consistent by the lower survival rate of the NTH1 deletion strain in human macrophages. No significant phenotype was observed for Nth2. The triple deletion strain was unable to establish a stable colonization of the gastrointestinal (GI) tract in mice indicating the importance of having trehalase activity for colonization in the gut

The involvement of the Candida glabrata

Candida glabrata is an opportunistic human fungal pathogen and is frequently present in the human microbiome. It has a high relative resistance to environmental stresses and several antifungal drugs. An important component involved in microbial stress tolerance is trehalose. In this work, we characterized the three C. glabrata trehalase enzymes Ath1, Nth1 and Nth2. Single, double and triple deletion strains were constructed and characterized both in vitro and in vivo to determine the role of these enzymes in virulence. Ath1 was found to be located in the periplasm and was essential for growth on trehalose as sole carbon source, while Nth1 on the other hand was important for oxidative stress resistance, an observation which was consistent by the lower survival rate of the NTH1 deletion strain in human macrophages. No significant phenotype was observed for Nth2. The triple deletion strain was unable to establish a stable colonization of the gastrointestinal (GI) tract in mice indicating the importance of having trehalase activity for colonization in the gut