Influence of Iron on Murine Malaria

铁对小鼠疟疾的影响

基本信息

批准号：
8124884
负责人：
DAVID Joseph SULLIVAN
金额：
$ 19.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2013-07-31
项目状态：
已结题

项目摘要

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

描述（由申请人提供）：已证明铁充足儿童补充铁会增加与疟疾相关的发病率，但铁缺乏儿童则不会。尽管受感染的红细胞中存在毫摩尔血红素铁，但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。铁补充尚未在小鼠疟疾模型中得到充分评估。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，这对人类营养铁补充剂的影响。我们假设寄生虫生物可利用铁过量对疟疾肝脏阶段的影响显着大于对疟疾红细胞阶段的影响。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。具体目标是 1) 比较肝期疟疾和红细胞期疟疾缺铁小鼠和铁充足小鼠的铁补充类型和疟疾感染时间； 2) 评估补铁和疟疾感染时机对基因型铁缺陷小鼠的影响铁调素或红细胞（而非肝脏）铁吸收，3) 将疟疾结果与铁调素、红细胞铁蛋白和鼠锌原卟啉 IX 等血液生物标志物或干扰素-γ 等免疫生物标志物相关联。所使用的技术包括小鼠疟疾测试、铁分析和生物标志物测定。这些研究将能够将红细胞铁状态与补充铁的疟疾结果中的宿主免疫反应区分开来。其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，这对有疟疾风险的儿童的人类营养铁补充剂具有影响。公共健康相关性：本研究将调查补充铁对小鼠疟疾模型的影响。将在缺铁、铁充足和铁缺陷小鼠中评估补充铁的类型以及补充铁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。与结果相关的血液学和免疫学生物标志物将相互关联