Phosphate and Inositol Pyrophosphate Metabolism in Candida albicans

白色念珠菌是一种条件致病真菌，是人类真菌感染的主要原因 感染.它作为共生体存在于皮肤和粘膜组织（口腔、胃肠道）上 道和泌尿生殖道）。但据 引起浅表粘膜感染和危及生命的全身感染， 尤其是免疫力低下的人。每年有超过40万人被感染 全世界有危及生命的感染，死亡率在47- 75%之间，尽管 抗真菌治疗。我们发现念珠菌感染对磷酸盐限制的反应是 变成丝状的和有毒的。丝状形成包括菌丝的形成， 帮助酵母细胞清除营养物质的形态结构。In C.白色念珠菌 丝状形式是毒力所必需的。 磷酸盐代谢和体内平衡对于细菌中所有细胞的存活至关重要 和酵母对植物和动物的作用。寄生真菌病原体必须从 人类宿主，这种摄取对于毒性至关重要。另一方面，过多的磷酸盐 是细胞毒性的，细胞维持磷酸盐稳态的机制（PHO途径）。 体内平衡涉及磷酸盐清除剂，无机磷酸盐（Pi）转运蛋白， Pi聚合成聚磷酸盐，以及聚磷酸盐在液泡中的储存。表达 当Pi变得有限时，编码这些蛋白质的基因的数量会增加。磷酸 限制还影响第二个途径，雷帕霉素靶向（TOR）途径， 营养丰富的增殖。TOR通路增加促生长因子的表达， 营养丰富时的基因，营养有限时的应激反应基因。的 TOR途径调节真菌病原体的形态发生途径。 最近的证据表明，肌醇焦磷酸调节PHO和TOR 影响磷酸盐稳态和增殖的途径。肌醇焦磷酸是 在所有真核生物中发现的携带高能量的细胞内信号分子。路口 磷酸盐稳态，增殖，形态发生和肌醇焦磷酸之间的关系， 在白色念珠菌中研究不足。我提议将我实验室在肌醇方面的专长与联合收割机 焦磷酸盐代谢与我们的专业知识，在C。白色念珠菌病理生物学，以解决以下问题 假设：肌醇焦磷酸调节磷酸盐稳态和TOR信号转导， 白念珠菌对磷酸盐限制的反应影响形态学和毒力。

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.