USE OF DISTINCT IRON UPTAKE SYSTEMS BY CANDIDA ALBICANS

描述（由申请人提供）：白色念珠菌（Ca）是一种常见的机会性真菌病原体，在免疫功能低下的患者中引起严重感染。耐药性正在增加，有必要确定新的药物靶点。铁获取已被证明是细菌毒力的一个重要因素，对于Ca来说也是如此。在小鼠模型中，缺乏CaFTR1铁渗透酶的敲除突变体是无毒的。我们发现，事实上，钙使用三种基因和生物化学上不同的铁摄取系统。一个需要CaFTR1的还原系统能够还原和释放铁螯合物，包括转铁蛋白螯合物。铁载体系统介导铁素载体螯合物的摄取，并需要铁载体转运体CaSIT1。最后，血红素铁利用系统需要由CaHMXl编码的血红素加氧酶。

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.