Pathogenesis of falciparum malaria in infancy

描述（由申请方提供）：疟疾导致100万非洲人死亡 孩子们每年。然而，尽管在完全流行地区的所有婴儿都发展为 寄生虫血症频繁，只有10%的发展严重贫血，最常见的 死因了我们先前表明，寄生虫粘附和抗粘附 抗体解释了妊娠期疟疾的易感性和抵抗力。因为 感染儿童的寄生虫的结合表型不同于 感染成年人，我们假设，一个类似的范式解释了 婴儿疟疾的发病机制。 我们建议对婴儿从出生到3岁进行纵向研究。我们将 检查样本：1）恶性疟原虫粘附表型; 2）抗粘附 抗体; 3）血红蛋白（Hb）Fvs含HbA的 (i.e.,胎儿与母体）红细胞; 4）对氨基苯甲酸（PABA）水平， HbF和抗体。我们将测试我们的基本假设， 抗粘附抗体预示着严重的婴儿期疟疾。另外我们 将检验一个次要假设，即新生儿对疟疾有抵抗力， 因为它们的脉管系统不支持寄生虫结合。基于我们 假设，我们预期以下结果：1）寄生虫粘附表型 随着宿主年龄的变化; 2）抗粘附抗体保护婴儿免受 具有相应粘附表型的寄生虫; 3）寄生虫结合 模式和特定的抗粘附抗体预测保护严重 贫血; 4）脐带血寄生虫将结合CSA， 仅在新生儿的含HbA的红细胞中; 5）基因型和 脐带血分离株和获得的分离株之间的结合表型不同 在婴儿第一次感染的时候 我们将研究其他因素对疟疾的影响，包括 经皮转移的母体抗体、HbF和PABA水平，我们 将HIV状态确定为这些研究中的潜在混杂因素。如果 母乳喂养通过限制对氨基苯甲酸的摄入而赋予对疟疾的抵抗力，这将 影响关于热带地区感染艾滋病毒的妇女是否应该 胸部。这些研究将确定寄生虫粘附的作用， 抗粘附抗体在婴儿疟疾发病机制中的作用， 确定儿童抗疟治疗的新目标。确定新 儿童治疗是一个紧迫的公共卫生目标，但不是一个资金 这是美国国防部的优先事项。

DESCRIPTION (provided by the applicant): Malaria kills 1 million African children each year. However, although all infants in holoendemic areas develop parasitemia frequently, only 10 percent develop severe anemia, the commonest cause of death. We previously showed that parasite adhesion and anti-adhesion antibodies explain susceptibility and resistance to pregnancy malaria. Because the parasites infecting children have binding phenotypes distinct from those infecting adults, we hypothesize that a similar paradigm explains the pathogenesis of infancy malaria. We propose a longitudinal study of infants from birth through age 3. We will examine samples for: 1) P. falciparum adhesion phenotype; 2) anti-adhesion antibodies; 3) presence of parasites in hemoglobin (Hb)Fvs HbA-containing (i.e., fetal vs. maternal) red cells; 4) levels of p-amino benzoic acid (PABA), HbF, and antibodies. We will test our primary hypothesis that parasite binding and anti-adhesion antibodies predict severe infancy malaria. In addition, we will examine a secondary hypothesis that neonates are resistant to malaria because their vasculature does not support parasite binding. Based on our hypotheses, we expect the following results: 1) parasite adhesion phenotypes change with host age; 2) anti-adhesion antibodies protect infants from parasites with the corresponding adhesion phenotype; 3) parasite binding patterns and specific anti-adhesion antibodies predict protection from severe anemia; 4) cord blood parasites will bind CSA, and parasites will appear exclusively in HbA-containing red cells of neonates; 5) the genotype and binding phenotype will differ between cord blood isolates and isolates obtained at the time of an infant's first infection. We will examine other factors for their effect on malaria, including transpiacentally transferred maternal antibodies, HbF, and PABA levels, and we will determine HIV status as a potential confounder in these studies. If breastfeeding confers resistance to malaria by limiting PABA intake, this will influence the debate on whether HIV-infected women in tropical areas should breastteed. These studies will establish the roles of parasite adhesion and anti-adhesion antibodies in the pathogenesis of infancy malaria, and may identify new targets for antimalarial therapies in children. Identifying new therapies for children is an urgent public health goal, but is not a funding priority for the United States Department of Defense.