Pathogenesis of falciparum malaria in infancy

婴儿期恶性疟疾的发病机制

• 批准号: 6532906
• 负责人: PATRICK E DUFFY
• 金额: $ 64.21万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532906
• 关键词: African; Plasmodium falciparum; cell adhesion molecules; chondroitin sulfates; clinical research; erythrocytes; female; genotype; hemoglobin As; hemoglobin F; host organism interaction; human pregnant subject; human subject; infant human (0-1 year); longitudinal human study; malaria; microorganism immunology; molecular pathology; pathologic process; polymerase chain reaction; pregnancy infection; preschool child (1-5); protein binding; receptor binding; receptor expression; surface antigens

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.

描述(由申请人提供)：疟疾导致100万非洲人死亡 每年都有孩子。然而，尽管全流行地区的所有婴儿都发育 寄生虫血症频繁，只有10%患上严重贫血，最常见 死因是。我们之前证明了寄生虫的黏附和抗黏附 抗体解释了对妊娠疟疾的易感性和抵抗力。因为 感染儿童的寄生虫具有不同于 感染成人，我们假设类似的范式解释了 婴幼儿疟疾的发病机制。 我们建议对婴儿从出生到3岁进行纵向研究。 检测样本：1)恶性疟原虫黏附表型；2)抗黏附 抗体；3)含HBA的血红蛋白(Hb)抗体中寄生虫的存在 (即胎儿与母体)红细胞；4)对氨基苯甲酸(PABA)水平， HBF和抗体。我们将测试我们最初的假设，即寄生虫结合 抗黏附抗体可以预测严重的婴儿期疟疾。此外，我们 将检验第二个假设，即新生儿对疟疾具有抵抗力 因为它们的血管系统不支持寄生虫结合。基于我们的 假设，我们期望得到以下结果：1)寄生虫黏附表型 随宿主年龄变化；2)抗黏附抗体保护婴儿免受 具有相应黏附表型的寄生虫；3)寄生虫结合 模式和特异性抗黏附抗体可预测对重症 4)脐带血寄生虫会与CsA结合，从而出现寄生虫 仅在新生儿含HBA的红细胞中；5)基因和 脐带血分离株和获得的分离株的结合表型不同 在婴儿第一次感染时。 我们将研究它们对疟疾产生影响的其他因素，包括 经皮转移的母体抗体、HBF和PABA水平，以及我们 将在这些研究中将艾滋病毒状况确定为一个潜在的混杂因素。如果 母乳喂养通过限制PABA的摄入量来增强对疟疾的抵抗力 影响热带地区感染艾滋病毒的妇女是否应该 戴着胸罩。这些研究将确定寄生虫黏附和 抗黏附抗体在婴幼儿疟疾发病机制中的作用 确定儿童抗疟疾治疗的新靶点。确定新的 儿童治疗是一项紧迫的公共卫生目标，但不是一项资金 美国国防部的优先事项。