Iron Deficiency Anemia and the Pathogenesis of Falciparum Malaria

描述（由申请人提供）：缺铁性贫血和疟疾是相互关联的全球卫生问题。缺铁性贫血在发展中国家的孕妇和儿童中造成严重的健康缺陷，需要补充铁。矛盾的是，证据表明IDA可以防止恶性疟原虫疟疾感染。因此，对补铁的需求在疟疾流行地区造成了公共卫生困境。在生理上，IDA改变了红细胞生成和红细胞（RBC）以及先天免疫功能，这可能在很大程度上影响恶性疟原虫感染的症状性红细胞阶段。尽管流行病学数据表明，补充铁会增加疟疾易感性，但风险的大小和生物学特性仍不确定。以前人们认为缺铁通过缺铁抑制疟疾的生长，其他病原体也是如此。然而，我们的工作为缺铁对寄生虫生长的影响提供了一种新的解释。我们的初步数据显示，恶性疟原虫侵入IDA红细胞的频率和复制效率较低，这表明红细胞特性和红细胞种群结构的变化驱动了IDA对疟疾的抗性。然而，IDA耐药的精确分子机制仍然未知。长期目标是进一步了解赋予疟疾感染抗性的人红细胞生理学的自然变化，以便指导疟疾流行地区的IDA管理。我们的首要假设是，由宿主缺铁引起的人类红细胞生理的自然改变降低了疟疾寄生虫入侵和在IDA红细胞中生长的能力。具体来说，我们将定义IDA RBC膜的生理特性，以减少寄生虫的分裂子阶段的入侵（AIM 1）。此外，我们将评估寄生虫是否使用不同的红细胞入侵途径来感染IDA红细胞，并确定受宿主缺铁影响的分裂子红细胞入侵的精确步骤（AIM 2）。该提案的目的是确定用于预防疟疾感染的IDA红细胞的关键分子特性。这对于规划如何避免疟疾流行地区补铁带来的风险至关重要。此外，与血红蛋白病一样，利用IDA的天然耐药性可以更好地了解寄生虫的发病机制，并确定血期疫苗和药物靶点。最后，有了这个精心构建的研究和培训计划，学员将

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.