Phosphate and Inositol Pyrophosphate Metabolism in Candida albicans

白色念珠菌中的磷酸盐和肌醇焦磷酸代谢

基本信息

批准号：
10580205
负责人：
RONDA J ROLFES
金额：
$ 45.88万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580205
关键词：
Address Affect Affinity Animals Antifungal Agents Attenuated Bacteria Binding Biological Assay Biology Candida Candida albicans Carbon Cell Nucleus Cells Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Diphosphates Drug Targeting Environment Enzymes Eukaryota Family Filament Gastrointestinal tract structure Gene Expression Genes Growth Guanosine Triphosphate Phosphohydrolases Heat Stress Disorders High Pressure Liquid Chromatography Homeostasis Human Human body Hyphae Immunocompromised Host Individual Infection Inorganic Phosphate Transporter Inositol Invertebrates Knowledge Life Link Liquid substance Measures Metabolism Microbial Biofilms Modeling Morphogenesis Morphology Mucous Membrane Mutate Mutation Mycoses Nitrogen Nutrient Oral cavity Oxidative Stress Induction Pathogenicity Pathway interactions Persons Phospho-Specific Antibodies Phosphoric Monoester Hydrolases Phosphorus Phosphorylation Phosphotransferases Plants Polymers Polyphosphates Proliferating Proteins Radiolabeled Regulation Research Ring Finger Domain Route Saccharomyces cerevisiae Side Signal Pathway Signal Transduction Signaling Molecule Sirolimus Skin Tissue Solid Structure System Systemic infection Tertiary Protein Structure Testing Vacuole Virulence Virulent Western Blotting Work Yeasts biological adaptation to stress cytotoxic detection of nutrient inorganic phosphate mortality mutant myoinositol novel pathogenic fungus polymerization response trait transcription factor ubiquitin ligase uptake urogenital tract

项目摘要

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.

白色念珠菌是一种机会性真菌病原体，也是人类真菌的主要原因感染。它驻留在皮肤和粘膜组织上（口腔，胃肠道大多数健康个体中人体的道和泌尿生殖道。但是，是负责引起表面粘膜感染和威胁生命的全身感染，特别是在免疫功能低下。每年有40万人感染40万人尽管有威胁生命的感染和死亡率在47-75％之间，尽管抗真菌治疗。我们发现念珠菌感染对磷酸盐的限制作出了反应变成丝状和毒气。细丝由菌丝形成，形态结构有助于酵母细胞清除营养。在白色念珠菌中丝状形式对于病毒是必需的。磷酸盐的代谢和稳态对于所有细胞中所有细胞的存活至关重要和酵母植物和动物。机会性真菌病原体必须从人类宿主，这种摄取对于病毒至关重要。在另一侧，磷酸盐过多是细胞毒性的，细胞维持磷酸盐稳态（PHO途径）的机制。稳态涉及磷酸盐清除剂，无机磷酸盐（PI）转运蛋白， PI聚合到聚磷酸盐中，并在真空中储存聚磷酸盐。表达当PI限制时，编码这些蛋白质的基因会增加。磷酸盐限制还会影响第二个途径，即拉帕霉素（Tor）途径，该途径连接营养丰富的增殖。 TOR途径增加了促增长的表达当营养丰富的基因，而当营养限制时，应力反应基因。 TOR途径调节真菌病原体中的形态发生途径。最近的证据表明，肌醇焦磷酸盐调节Pho和tor 影响磷酸盐稳态和增殖的途径。肌醇焦磷酸盐为在所有真核生物中发现的高能携带，细胞内信号分子。十字路口在磷酸盐稳态，增殖，形态发生和肌磷酸磷酸盐之间在白色念珠菌中进行了研究。我建议将实验室在inositel方面的专业知识结合在一起焦磷酸代谢具有我们在白色念珠菌病理生物学方面的专业知识，以解决以下假设：肌醇焦磷酸盐调节磷酸稳态和TOR信号传导白色念珠菌对磷酸盐限制的反应，以影响形态和病毒。