USE OF DISTINCT IRON UPTAKE SYSTEMS BY CANDIDA ALBICANS

白色念珠菌使用独特的铁吸收系统

基本信息

批准号：
7371105
负责人：
ANDREW B. DANCIS
金额：
$ 31.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7371105
关键词：
Adherence Affect Antibodies Attention Bacteria Behavior Biochemical Biological Models Candida albicans Candidiasis Cell Communication Cells Chimeric Proteins Complex Condition DNA Microarray Chip DNA Microarray format Dose Drug Delivery Systems Drug resistance Endothelial Cells Environment Epithelial Ferrichrome Gene Expression Genes Green Fluorescent Proteins Growth Heme Heme Iron Histology Human Immunocompromised Host Incubated Individual Infection Intravenous Iron Iron Chelating Agents Knock-out Laboratories Measures Mediating Modeling Mus Nutrient Oropharyngeal Oxidative Stress Oxygen Oxygenases Pathway interactions Phagocytosis Phase Phenotype Porphyrins Property Proteins Reagent Regulation Reporter Siderophores Source Stress System Testing Transferrin Umbilical vein Virulence Virulence Factors Virulent Work deprivation ferric citrate follow-up heme a hydroxamate monolayer mouse model mutant neutrophil pathogen permease promoter response uptake

项目摘要

DESCRIPTION (provided by applicant): Candida albicans (Ca) is a common opportunistic fungal pathogen that causes serious infections in immunocompromised patients. Drug resistance is increasing, and there is a need to identify new drug targets. Iron acquisition has been shown to be an important factor for virulence of bacteria, as well as for Ca. Knockout mutants lacking the CaFTR1 iron permease are avirulent in mouse models. We have found that Ca, in fact, uses three genetically and biochemically distinct iron uptake systems. A reductive system, requiring CaFTR1, is able to reduce and release ferric iron chelates, including transferrin chelates. A siderophore system mediates uptake of ferrisiderophore chelates of the ferrichrome type and requires the siderophore transporter CaSIT1. Finally, a heme iron utilization system requires heme oxygenase encoded by CaHMXl. In Aim1 usage of the different systems will be tested under varied types of stress by measuring iron uptake from different substrates and by measuring expression of CaSIT1, CaFTR1 and CaHMX1. Deletion strains lacking in one of the iron uptake systems will be tested for growth properties, phenotypes and sensitivities. In Aim 2, usage of the different uptake systems will be evaluated in model systems that include a model of oropharyngeal (epithelial) candidiasis, endothelial cell invasion, neutrophil interaction and intravenous infection of mice. Knockouts lacking individual uptake systems will be evaluated for their behavior in these model systems, with attention to deficits that may alter virulence. Finally in Aim 3, microarrays will be used to examine the effects of iron uptake from different iron sources (via different uptake systems) on expression of virulence genes. The hypothesis of this work is that different iron acquisition pathways are active in different host environments and may mediate virulent infections in those settings.

描述（由申请人提供）：白色念珠菌（CA）是一种常见的机会真菌病原体，会引起免疫功能低下患者的严重感染。耐药性正在增加，需要鉴定新的药物靶标。铁的获取已被证明是细菌毒力的重要因素。在小鼠模型中，缺乏CAFTR1铁渗透酶缺乏CAFTR1铁渗透酶的敲除突变体。我们发现CA实际上使用了三种遗传和生化不同的铁摄取系统。需要CAFTR1的还原系统能够减少和释放包括转铁蛋白螯合物在内的铁螯合物。铁载体系统介导了铁晶体类型的铁丝体螯合物的摄取，并且需要铁载体转运蛋白Casit1。最后，血红素铁的利用系统需要由CAHMXL编码的血红素加氧酶。在AIM1中，通过测量不同底物的铁吸收并测量Casit1，Caftr1和CaHMX1的表达，将在不同类型的应力下进行测试。其中一种铁摄取系统缺乏删除菌株，将测试生长特性，表型和敏感性。在AIM 2中，将在包括口咽（上皮）念珠菌，内皮细胞侵袭，中性粒细胞相互作用和小鼠静脉内感染的模型模型中评估不同摄取系统的使用。在这些模型系统中，将评估缺乏单个吸收系统的敲除系统的行为，并注意可能改变毒力的缺陷。最后，在AIM 3中，微阵列将用于检查来自不同铁源（通过不同摄取系统）对毒力基因表达的影响。这项工作的假设是，不同的铁采集途径在不同的宿主环境中活跃，并且可能介导这些环境中的有毒感染。