Iron Deficiency Anemia and the Pathogenesis of Falciparum Malaria

说明(申请人提供)：缺铁性贫血和疟疾是相互关联的全球卫生问题。缺铁性贫血(IDA)在发展中国家造成孕妇和儿童严重的健康缺陷，需要补充铁。矛盾的是，有证据表明IDA可以预防恶性疟原虫感染。因此，对铁补充剂的需求在疟疾流行地区造成了公共卫生困境。从生理上讲，IDA改变了红细胞生成和红细胞(RBC)以及先天免疫功能，这可能会对恶性疟原虫感染的RBC阶段产生相当大的影响。尽管流行病学数据表明，补铁增加了疟疾的易感性，但风险的大小和生物学仍不确定。以前，人们认为缺铁通过缺铁抑制疟疾的生长，就像其他病原体一样。然而，我们的工作为缺铁对寄生虫生长的影响提供了一个新的解释。我们的初步数据显示，恶性疟原虫在IDA红细胞中入侵和复制的频率较低，这表明RBC属性和RBC群体结构的变化推动了IDA对疟疾的抵抗力。尽管如此，IDA耐药的确切分子机制仍不清楚。长期目标是进一步了解对疟疾感染具有抵抗力的人类红细胞生理的自然变化，以便指导疟疾流行地区的IDA管理。我们的主要假设是，宿主铁缺乏引起的人类红细胞生理的自然变化降低了疟疾寄生虫在IDA红细胞中入侵和生长的能力。具体地说，我们将定义IDA红细胞膜的生理特性，以减少寄生虫裂殖子阶段的入侵(AIM 1)。此外，我们还将评估寄生虫是否通过不同的红细胞侵袭途径感染IDA红细胞，并确定宿主缺铁影响裂殖子红细胞侵袭的确切步骤(S)。该提案旨在确定IDA红细胞用于预防疟疾感染的关键分子特性。这对于规划如何避免疟疾流行地区补充铁带来的风险至关重要。此外，与血红蛋白疾病一样，IDA的天然抵抗力可以被用来更好地了解寄生虫的发病机制，并确定血液期疫苗和药物靶点。最后，通过这个精心设计的研究和培训计划，学员将 发展分子生物学和寄生虫学方面的高级技能，包括研究设计、数据收集和分析；以及获得临床和翻译研究技能，以促进传染病临床和研究兴趣的整合。

DESCRIPTION (provided by applicant): Iron deficiency anemia and malaria are interconnected global health concerns. Iron deficiency anemia (IDA) causes significant health deficits in pregnant women and children in the developing world and requires iron supplementation. Paradoxically, evidence suggests IDA protects against Plasmodium falciparum malaria infection. Thus the need for iron supplementation creates a public health dilemma in malaria endemic areas. Physiologically, IDA alters erythropoiesis and red blood cells (RBCs) as well as innate immune function, which may considerably impact the symptomatic RBC stage of P. falciparum infection. Though epidemiological data suggest iron supplementation increases malaria susceptibility, the magnitude and biology of risk remain uncertain. Previously it was believed iron deficiency inhibited malaria growth through iron deprivation, as is the case with other pathogens. However, our work has generated a novel explanation for the effect of iron deficiency on parasite growth. Our preliminary data showing P. falciparum less frequently invades and replicates less efficiently in IDA RBC suggest changes in RBC properties and the RBC population structure drive IDA resistance to malaria. Still, the precise molecular mechanisms of IDA resistance remain unknown. The long term goal is to further understand natural alterations in human RBC physiology that confer resistance to malaria infection, in order to direct IDA management in malaria endemic areas. Our overarching hypothesis is that natural alterations in human RBC physiology caused by host iron deficiency reduce the ability of malaria parasites to both invade and grow in IDA RBCs. Specifically, we will define the physiological properties of IDA RBC membranes that reduce invasion by the merozoite stage of the parasite (AIM 1). In addition, we will assess whether the parasite uses different RBC invasion pathways to infect IDA RBCs and determine the precise step(s) in merozoite RBC invasion impacted by host iron deficiency (AIM 2). The proposal aims will determine the critical molecular properties of IDA RBCs that serve to protect against malaria infection. This is essential in planning how to avoid risks accompanying iron supplementation in malaria endemic areas. Furthermore, like the hemoglobinopathies, natural resistance of IDA can be exploited to better understand parasite pathogenesis and identify blood stage vaccine and drug targets. Finally, with this carefully constructed research and training plan, the trainee will develop advanced skills in molecular biology and parasitology, including research design, data collection, and analysis; as well as acquire clinical and translational research skills to facilitae integration of clinical and research interests in infectious diseases.