Phosphate Acquisition and Virulence in Human Fungal Pathogens

Abstract

The ability of pathogenic fungi to acquire essential macro and micronutrients during infection is a well-established virulence trait. Recent studies in the major human fungal pathogens Candida albicans and Cryptococcus neoformans have revealed that acquisition of the essential macronutrient, phosphate, is essential for virulence. The phosphate sensing and acquisition pathway in fungi, known as the PHO pathway, has been extensively characterized in the model yeast Saccharomyces cerevisiae. In this review, we highlight recent advances in phosphate sensing and signaling mechanisms, and use the S. cerevisiae PHO pathway as a platform from which to compare the phosphate acquisition and storage strategies employed by several human pathogenic fungi. We also explore the multi-layered roles of phosphate acquisition in promoting fungal stress resistance to pH, cationic, and oxidative stresses, and describe emerging roles for the phosphate storage molecule polyphosphate (polyP). Finally, we summarize the recent studies supporting the necessity of phosphate acquisition in mediating the virulence of human fungal pathogens, highlighting the concept that this requirement is intimately linked to promoting resistance to host-imposed stresses.

Accessibility and contribution to glucan masking of natural and genetically tagged versions of yeast wall protein 1 of Candida albicans

“…Even though nutrient limitation in general does not appear to upregulate YWP1 expression, sulfur limitation has recently been found to result in substantial induction of YWP1 , although not to the same extent as phosphate limitation. Although both phosphate and sulfate can bind to the same protein domains, it seems likely that phosphate homeostasis is controlled by intermediary inositol polyphosphate signaling molecules [ 121 , 122 ], and that sulfur sensing and response involve independent pathways [ 123 ]. The effect of sulfur starvation on epitope accessibility has not yet been investigated for C .…”

Phosphate in Virulence of Candida albicans and Candida glabrata

“…This review focuses on the role of phosphate homeostasis in virulence of Candida albicans and C. glabrata, the most frequently isolated fungal species causing invasive disease in humans. Excellent reviews of the role of phosphate in virulence of other fungi have appeared [1,2] so we here focus on recent findings in Candida. C. albicans, the main focus of this review, colonizes oral and gastrointestinal mucous membranes in 40%-75% of healthy individuals [3][4][5].…”

“…In pathogenic bacteria, phosphate acquisition is known to be crucial in virulence [20][21][22]. A recent superb review compares the S. cerevisiae PHO regulon with those of its elements known to be conserved in C. albicans and other human fungal pathogens [1]. The activity of many of these elements is only beginning to be characterized, and novel components remain to be discovered, but in broad strokes, the PHO regulon of these fungi resembles that of S. cerevisiae [23].…”

Nutritional Requirements and Their Importance for Virulence of Pathogenic Cryptococcus Species

“…Phosphate is essential for many cellular functions from kinase signalling to energy production and storage. Cryptococcus , like other pathogenic fungi examined, has a conserved phosphate uptake pathway that is absent in human cells [ 160 ]. Deletion of the transcriptional regulator of acquisition, Pho4, results in a failure to grow in the absence of added phosphate and with phosphate in alkaline and host (pH 7.4) conditions [ 161 ].…”