CYTOADHERENCE IN MATERNAL MALARIA

描述(申请人提供)：在孕妇中，感染恶性疟原虫(IRBCs)的红细胞选择性地附着在孕妇的胎盘上，导致几种临床症状，包括出生体重低、死产、胎儿流产、母亲贫血和死亡。大量研究表明，胎盘IRBC的黏附是由4-硫酸软骨素(C4S)介导的。在之前的资助期间，已经证实一种独特的低硫化硫酸软骨素蛋白多糖(CSPG)是胎盘中IRBC黏附的天然受体。确定了C4S在这一过程中的几个关键结构元素。与现有的关于C4S结构相互作用的信息水平相比，人们对红细胞表面寄生虫黏附蛋白知之甚少。胎盘红细胞黏附的另一个尚未完全了解的方面是额外受体的可能作用。近年来，透明质酸与胎儿Fc受体已有关联，但它们的作用尚不清楚。这项研究的长期目标是描绘胎盘红血球附着所涉及的结构相互作用，并利用这一知识开发治疗胎盘性疟疾的药物和/或疫苗。为了实现这一目标，必须明确鉴定寄生虫黏附蛋白并确定其黏附结构域。因此，本提案的目的是调查三个重要方面，这三个方面代表了前一个批准期内研究的合乎逻辑的延伸。(1)充分确定参与红细胞黏附的C4S结构元素。利用结构确定的C4S十二糖制备光亲和探针。采用光亲和层析法分离寄生虫黏附蛋白，并对其进行生化鉴定。(2)通过功能基因组学方法和C4S-IRBC黏附抑制分析，对寄生虫S蛋白进行鉴定和鉴定。(3)通过检测大量恶性疟原虫感染胎盘的血样，确定透明质酸和胎儿Fc受体是否也参与了胎盘IRBC黏附。

DESCRIPTION (provided by the applicant): In pregnant women, red blood cells infected with Plasmodium falciparum (IRBCs) selectively adhere in the pregnant women, placenta, causing several clinical manifestations including low birth weight, stillbirth, abortion of the fetus, and anemia and death in the mother. A number of studies have shown that the placental IRBC adherence is mediated by chondroitin 4-sulfate (C4S). During the previous grant period, it was established that a uniquely low sulfated chondroitin sulfate proteoglycan (CSPG) is the natural receptor for IRBC adherence in the placenta. Several critical structural elements of C4S involved in the process were determined. In contrast to the level of information available on the C4S structural interactions, very little is known about the parasite adhesive protein on the IRBC surface. Another aspect of the placental IRBC adherence that is not fully understood is the possible role of additional receptors. Recently, hyaluronic acid and fetal Fc receptor have been implicated, but their roles remain unclear. The long-term objective of this investigation is to delineate the structural interactions involved in the placental IRBC adherence, and use this knowledge to develop therapeutics and/or a vaccine for placental malaria. To accomplish this goal, the parasite adhesive protein has to be unequivocally identified and its adhesive domain determined. Therefore, the aims of this proposal are to investigate three important aspects that represent logical extensions of the studies during the previous granting period. (1) Determine fully the C4S structural elements involved in IRBC adhesion. Prepare photo-affinity probe using the structurally defined C4S dodecasaccharide. Isolate the parasite adhesive protein by photo-affinity tagging and by C4S-affinity chromatography and characterize biochemically. (2) Identify and characterize the parasite protein(s) by functional genomic approaches, and by C4S-IRBC adhesion inhibition analysis using antibodies against identified proteins. (3) Determine whether hyaluronic acid and fetal Fc receptor also mediate placental IRBC adhesion by testing blood samples from a large number of P. falciparum-infected placentas.