Phosphate in Virulence of Candida albicans and Candida glabrata

Abstract

Candida species are the most commonly isolated invasive human fungal pathogens. A role for phosphate acquisition in their growth, resistance against host immune cells, and tolerance of important antifungal medications is becoming apparent. Phosphorus is an essential element in vital components of the cell, including chromosomes and ribosomes. Producing the energy currency of the cell, ATP, requires abundant inorganic phosphate. A comparison of the network of regulators and effectors that controls phosphate acquisition and intracellular distribution, the PHO regulon, between the model yeast Saccharomyces cerevisiae, a plant saprobe, its evolutionarily close relative C. glabrata, and the more distantly related C. albicans, highlights the need to coordinate phosphate homeostasis with adenylate biosynthesis for ATP production. It also suggests that fungi that cope with phosphate starvation as they invade host tissues, may link phosphate acquisition to stress responses as an efficient mechanism of anticipatory regulation. Recent work indicates that connections among the PHO regulon, Target of Rapamycin Complex 1 signaling, oxidative stress management, and cell wall construction are based both in direct signaling links, and in the provision of phosphate for sufficient metabolic intermediates that are substrates in these processes. Fundamental differences in fungal and human phosphate homeostasis may offer novel drug targets.

Keywords: PHO regulon; Target of Rapamycin; antifungal; cell wall; drug target; metabolomics; oxidative stress resistance; virulence.

Figure 1

Model: Candida albicans phosphate (Pi) homeostasis maintenance. Under limited Pi conditions, Pi is imported by high-affinity transporters Pho84 and Pho89 whose pH optimum is in the acidic and alkaline range, respectively. Decreased Pi availability also activates the PHO regulon, whose central transcription factor Pho4 is dephosphorylated and localized to the nucleus. Independent of the interaction with the Pho2 homolog Grf10, Pho4 alone activates the expression of genes to maintain intracellular Pi homeostasis, including high-affinity Pi transporters (PHO84 and PHO89), polyphosphate synthesis complex (VTC1–4), glycerophosphodiester transporters (GIT1–3), glycerophosphocholine phosphodiesterase (GDE1), as well as acid phosphatases (PHO100, 112, and 113).

Figure 2

Model: Pho84 contributes to C. albicans TORC1 signaling, metabolism, cell wall integrity and oxidative stress defense. The high-affinity inorganic phosphate (Pi) transporter Pho84 plays a significant role in cellular import of Pi. Cytosolic and mitochondrial Pi becomes available to metabolic processes that produce substrates for cell wall construction enzymes (nucleotide sugars UDP-glucose and UDP-N-Acetylglucosamine, GlcNAc), the energy currency ATP, and co-factors with possible roles in detoxifying reactive oxygen species (ROS), i.e., thiamine pyrophosphate and erythro-ascorbic acid. Pho84 also contributes to oxidative stress management by activating TORC1 through Gtr1. TORC1 induces the expression of superoxide dismutase Sod3, contributing to C. albicans tolerance of ROS produced by host immune cells.