Adaptation of Candida albicans to Reactive Sulfur Species

Abstract

Candida albicans is an opportunistic fungal pathogen that is highly resistant to different oxidative stresses. How reactive sulfur species (RSS) such as sulfite regulate gene expression and the role of the transcription factor Zcf2 and the sulfite exporter Ssu1 in such responses are not known. Here, we show that C. albicans specifically adapts to sulfite stress and that Zcf2 is required for that response as well as induction of genes predicted to remove sulfite from cells and to increase the intracellular amount of a subset of nitrogen metabolites. Analysis of mutants in the sulfate assimilation pathway show that sulfite conversion to sulfide accounts for part of sulfite toxicity and that Zcf2-dependent expression of the SSU1 sulfite exporter is induced by both sulfite and sulfide. Mutations in the SSU1 promoter that selectively inhibit induction by the reactive nitrogen species (RNS) nitrite, a previously reported activator of SSU1, support a model for C. albicans in which Cta4-dependent RNS induction and Zcf2-dependent RSS induction are mediated by parallel pathways, different from S. cerevisiae in which the transcription factor Fzf1 mediates responses to both RNS and RSS. Lastly, we found that endogenous sulfite production leads to an increase in resistance to exogenously added sulfite. These results demonstrate that C. albicans has a unique response to sulfite that differs from the general oxidative stress response, and that adaptation to internal and external sulfite is largely mediated by one transcription factor and one effector gene.

Transcriptomic and chemogenomic analyses unveil the essential role of Com2-regulon in response and tolerance of Saccharomyces cerevisiae to stress induced by sulfur dioxide

“…The biological functions enriched in the dataset of SO 2 -induced genes are “amino acid metabolism”, “nitrogen and sulfur metabolism”, “metabolism of vitamins and prosthetic groups”, “ion transport”, “amino acid transport” and “interaction with the environment”, as detailed in Figure S2. In general, these functional classes coincide with those obtained in the prior transcriptomics analyses of S. cerevisiae SO 2 -stressed cells [31, 32] and also of C. albicans [33]. Despite this, our number of SO 2 -responsive genes was much higher than the one reported in other studies performed in S. cerevisiae [31, 32], which can be attributed to the higher sensitivity of the BY4741 strain in comparison with the susceptibility of the wine strains explored in these other studies [31, 32].…”

“…Although Com2 had been identified as the orphan-homologue of C. albicans Mnl1 they do not appear to respond to the same stimuli since Com2 is dispensable for tolerance and response to acetic acid [27, 29], while Mnl1 is essential for this response [26]. Furthermore, no significant over-representation of genes of the Mnl1-regulon was observed in a recent survey of C. albicans response to sulfite stress [33].…”

Combining Genome-Wide Gene Expression Analysis (RNA-seq) and a Gene Editing Platform (CRISPR-Cas9) to Uncover the Selectively Pro-oxidant Activity of Aurone Compounds Against Candida albicans

“…In C. rosea, the activation of the Ehrlich pathway and demethiolation in response to highly exogenous methionine was regulated by nitrogen catabolite repression (Xu et al, 2018). For C. albicans, in addition to up-regulation of the nitrogen catabolite repression pathway that is associated with sulfur amino acid catabolism (Chebaro et al, 2017), the arginine biosynthesis pathway has been linked to the urea cycle (Jastrzębowska and Gabriel, 2015). Under poor nitrogen supply, the arginine biosynthesis pathway is induced in order to regulate the urea amidolyase, Dur1,2 (expression up-regulated by ninefold), which converts excess nitrogen to CO 2 and ammonia in order to export the latter out of the cell through the up-regulated ammonia transport pumps (DUR3 1.8-fold, MEP1 3-fold, ATO5 4.7-fold, TOP2 1.8-fold, TPO4 1.6-fold, FLU1 2.6-fold, and RTA2 6.8-fold) (Vylkova et al, 2011).…”

The landscape of toxic intermediates in the metabolic networks of pathogenic fungi reveals targets for antifungal drugs

“…Interestingly, the acquisition of inorganic nitrogen and sulfur sources is not required for full virulence and assimilation of these elements is possible via multiple organic and inorganic substrates in pathogenic fungi like A. fumigatus or C. albicans [59][60][61]. However, a recent study shows that sulfite detoxification is actively controlled and enhances growth in C. albicans suggesting that the involved enzymes and regulators are suitable targets for antifungal interventions [62].…”