Influence of Iron on Murine Malaria

说明(申请人提供)：在铁充足而不是缺铁的儿童中补充铁已经被证明增加了疟疾相关的发病率。铁络合剂虽然对细菌和哺乳动物细胞具有细胞抑制作用，但实际上可以杀死疟疾寄生虫，尽管受感染的红细胞中含有毫米级的血红素铁。在小鼠疟疾模型中，铁的补充尚未得到充分的评估。广泛的长期目标是快速评估补铁的类型和补铁期间疟疾感染的时间对小鼠疟疾发病率的影响，以及对人类营养补铁的影响。我们假设寄生虫生物有效铁过量对肝期的影响明显大于疟疾的红细胞期。补铁的类型或补铁期间感染疟疾的时间将改变疟疾的结果，可能取决于铁对免疫功能的影响，而不是红细胞铁水平。具体目的是：1)比较缺铁和铁充足小鼠的补铁类型和感染疟疾的时间对肝脏和红细胞期疟疾的影响；2)评估补铁和感染疟疾的时机对基因型铁缺陷小鼠疟疾感染的影响 3)将疟疾预后与血液学生物标记物如海普西丁、红细胞铁蛋白和小鼠锌原卟啉IX或免疫生物标记物如干扰素-γ相关联。将利用的技术包括小鼠疟疾测试、铁图谱和生物标记物分析。这些研究将能够区分红细胞铁状态和宿主免疫反应在补充铁的疟疾结局中的作用。重大影响是快速评估铁疗法对小鼠疟疾发病率的方法和类型，以及对人类营养补铁对有疟疾风险的儿童的影响。 公共卫生相关性：这项研究将在小鼠疟疾模型中调查补铁的影响。将在缺铁、缺铁和缺铁小鼠身上评估补铁的类型和在肝脏阶段和血细胞阶段补充铁期间疟疾感染的时间。与预后相关的血液学和免疫学生物标志物将相互关联

DESCRIPTION (provided by applicant): Iron supplementation in iron replete, but not iron deficient children has been shown to increase malaria associated morbidity. Iron chelators, while cytostatic for bacterial and mammalian cells, actually kill malaria parasites, despite the availability of millimolar heme iron in the infected erythrocyte. Iron repletion has not been fully evaluated in murine malaria models. The broad long term objective is to rapidly evaluate the type of iron supplementation and timing of malaria infection during iron repletion on malaria morbidity in mice with implications for human nutritional iron supplementation. We hypothesize that parasite bioavailable iron excess influences the hepatic stage significantly more than erythrocytic stage of malaria. The type of iron supplementation or timing of malaria infection during iron replenishment will alter malaria outcome possibly dependent on an iron effect on immune function rather than the erythrocyte iron level. The specific aims are 1) to compare the type of iron supplementation and timing of malaria infection in iron deficient and iron replete mice on both hepatic and erythrocytic stage malaria; 2) to evaluate the influence of iron supplementation and timing of malaria infection in genotypic iron defective mice for hepcidin or also erythroid, not hepatic, iron uptake and 3) to correlate malaria outcomes with hematologic biomarkers like hepcidin, erythrocyte ferritin and murine zinc protoporphyrin IX or immunologic biomarkers like interferon-gamma. The techniques to be utilized include mouse malaria testing, iron profiling and biomarker assays. These studies will be able to distinguish erythrocyte iron status from host immune response in malaria outcome with iron supplementation. The significant impact is to rapidly evaluate the method and type of iron therapy on malaria morbidity in mice with implications for human nutritional iron supplementation for children at risk of malaria. PUBLIC HEALTH RELEVANCE: This research will investigate the influence of iron supplementation in a mouse malaria model. The type of iron supplementation and timing of malaria infection during iron repletion on liver stage and blood cell stage malaria outcomes will be evaluated in iron deficient, iron replete and iron defective mice. Hematologic and immunologic biomarkers associated with outcome will be correlated