Influence of Iron on Murine Malaria

描述（由申请人提供）：已证明铁充足但非缺铁儿童的铁补充剂会增加疟疾相关发病率。铁螯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原虫，尽管在受感染的红细胞中存在毫摩尔血红素铁。铁的补充尚未在鼠疟疾模型中得到充分评价。广泛的长期目标是快速评估铁补充剂的类型和铁补充期间疟疾感染的时间对小鼠疟疾发病率的影响，以及对人类营养性铁补充剂的影响。我们推测，寄生虫生物可利用铁过剩的影响，肝阶段显着超过红细胞期疟疾。补铁的类型或补铁期间疟疾感染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）比较铁缺乏和铁充足小鼠对肝期和红细胞期疟疾的补铁类型和疟疾感染时间; 2）评价基因型铁缺乏小鼠补铁和疟疾感染时间的影响， 铁调素或红系细胞而非肝的铁摄取，以及3）将疟疾结果与血液学生物标志物如铁调素、红细胞铁蛋白和鼠锌原卟啉IX或免疫学生物标志物如干扰素-γ相关联。将使用的技术包括小鼠疟疾检测、铁分析和生物标志物测定。这些研究将能够区分红细胞铁状态与宿主免疫反应，在疟疾的结果与铁补充剂。重要的影响是快速评估铁治疗的方法和类型对小鼠疟疾发病率的影响，对有疟疾风险的儿童进行人类营养铁补充。 公共卫生相关性：这项研究将调查铁补充剂在小鼠疟疾模型中的影响。将在缺铁、铁充足和铁缺陷小鼠中评价铁补充的类型和铁补充期间疟疾感染的时间对肝脏阶段和血细胞阶段疟疾结果的影响。与结局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