CYTOADHERENCE IN MATERNAL MALARIA

描述（由申请方提供）：在孕妇中，感染恶性疟原虫（IRBC）的红细胞选择性粘附在孕妇胎盘中，导致几种临床表现，包括低出生体重、死产、胎儿流产、母亲贫血和死亡。大量研究表明，胎盘IRBC粘附是由4-硫酸软骨素（C4 S）介导的。在之前的资助期间，确定了独特的低硫酸化硫酸软骨素蛋白聚糖（CSPG）是胎盘中IRBC粘附的天然受体。几个关键的C4 S结构元素参与的过程中被确定。与C4 S结构相互作用的信息水平相反，对IRBC表面上的寄生虫粘附蛋白知之甚少。胎盘IRBC粘附的另一个尚未完全理解的方面是其他受体的可能作用。最近，透明质酸和胎儿Fc受体已被牵连，但他们的作用仍不清楚。本研究的长期目标是描述胎盘IRBC粘附中涉及的结构相互作用，并利用这些知识开发胎盘疟疾的治疗方法和/或疫苗。为了实现这一目标，寄生虫粘附蛋白必须明确确定和其粘附结构域确定。因此，本提案的目的是调查代表上一个赠款期间研究的逻辑延伸的三个重要方面。(1)充分确定与IRBC粘附有关的C4 S结构要素。使用结构确定的C4 S十二糖制备光亲和探针。通过光亲和标记和C4 S亲和层析分离寄生虫粘附蛋白并进行生化表征。(2)通过功能基因组方法和使用针对所鉴定蛋白质的抗体的C4 S-IRBC粘附抑制分析来鉴定和表征寄生虫蛋白质。(3)通过检测大量恶性疟原虫感染胎盘的血液样本，确定透明质酸和胎儿Fc受体是否也介导胎盘IRBC粘附。

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.