Influence of Iron on Murine Malaria

描述（由申请人提供）：补铁而非缺铁儿童的补铁已被证明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疾寄生虫，尽管受感染的红细胞中存在毫摩尔血红素铁。在小鼠疟疾模型中尚未充分评估铁的补充。广泛的长期目标是快速评估铁补充类型和疟疾感染时间在铁补充期间对小鼠疟疾发病率的影响，并对人类营养铁补充有影响。我们假设疟原虫生物可利用铁过量对疟疾肝期的影响明显大于红细胞期。补铁的类型或补铁期间疟疾感染的时机将改变疟疾的结果，这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)比较缺铁和补铁小鼠在肝期和红细胞期疟疾感染的补铁类型和时机；2)评价补铁对基因型铁缺陷小鼠疟疾感染时间的影响

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