Phosphate and Inositol Pyrophosphate Metabolism in Candida albicans - Candida albicans is an opportunistic fungal pathogen and a major cause of human fungal infections. It resides as a commensal on the skin and mucosal tissues (oral cavity, gastrointestinal tract and urogenital tract) of the human body in most healthy individuals. However, it is responsible for causing superficial mucosal infections and life-threatening systemic infections, particularly in the immunocompromised. Upwards of 400,000 people are infected annually worldwide with life-threatening infections, and mortality rates ranging between 47-75%, in spite of anti-fungal treatments. We found that Candida infections respond to phosphate limitation by becoming filamentous and virulent. Filamentation consists of the formation of hyphae, morphological structures that aid the yeast cell in scavenging for nutrients. In C. albicans, the filamentous form is necessary for virulence. Phosphate metabolism and homeostasis is critical for the survival of all cells from bacteria and yeast to plants and animals. Opportunistic fungal pathogens must acquire phosphate from the human host, and this uptake is essential for virulence. On the other side, too much phosphate is cytotoxic, and cells maintain mechanisms for phosphate homeostasis (the PHO pathway). Homeostasis involves phosphate scavengers, inorganic phosphate (Pi) transporters, polymerization of Pi into polyphosphate, and storage of polyphosphate in the vacuole. Expression of the genes that encodes these proteins is increased when Pi becomes limiting. Phosphate limitation also affects a second pathway, the Target-of-Rapamycin (TOR) pathway, that links nutrient abundance to proliferation. The TOR pathway increases the expression of pro-growth genes when nutrients are abundant, and stress-response genes when nutrients are limiting. The TOR pathway regulates the morphogenesis pathways in fungal pathogens. Recent evidence suggests that inositol pyrophosphates regulate the PHO and TOR pathways to affect both phosphate homeostasis and proliferation. Inositol pyrophosphates are high-energy carrying, intracellular signaling molecules found in all eukaryotes. The intersection between phosphate homeostasis, proliferation, morphogenesis and inositol pyrophosphates is understudied in Candida albicans. I propose to combine my lab’s expertise in inositol pyrophosphate metabolism with our expertise in C. albicans pathobiology to address the following hypothesis: Inositol pyrophosphates regulate phosphate homeostasis and TOR signaling in response to phosphate limitation in Candida albicans to affect morphology and virulence.
