CYTOADHERENCE IN MATERNAL MALARIA

描述（由申请人提供）：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上，引起几种临床表现，包括低出生体重、死胎、胎儿流产、母亲贫血和死亡。许多研究表明，胎盘IRBC粘附是由硫酸软骨素（C4S）介导的。在之前的资助期间，已经确定了一种独特的低硫酸软骨素硫酸蛋白多糖（CSPG）是胎盘中IRBC粘附的天然受体。确定了参与该过程的C4S的几个关键结构元素。与C4S结构相互作用的现有信息水平相比，对IRBC表面的寄生虫粘附蛋白知之甚少。胎盘IRBC粘附性的另一个方面尚未完全了解是其他受体的可能作用。近年来，透明质酸与胎儿Fc受体有关联，但其作用尚不清楚。这项研究的长期目标是描述与胎盘IRBC粘附有关的结构相互作用，并利用这一知识开发治疗和/或胎盘疟疾的疫苗。为了实现这一目标，必须明确鉴定寄生虫粘附蛋白并确定其粘附结构域。因此，本提案的目的是调查三个重要方面，这些方面代表了前一个授权期间研究的逻辑延伸。(1)充分确定参与IRBC粘附的C4S结构元件。用结构确定的C4S十二糖制备光亲和探针。通过光亲和标记和c4s亲和层析分离出寄生虫黏附蛋白，并对其进行生化鉴定。(2)通过功能基因组方法鉴定和表征寄生虫蛋白，并使用针对鉴定蛋白的抗体进行C4S-IRBC粘附抑制分析。(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.