CYTOADHERENCE IN MATERNAL MALARIA

最近的研究表明，在孕妇感染疟疾期间，胎盘通过与4-硫酸软骨素(C4S)结合来选择恶性疟原虫的一个亚群。在疟疾流行地区，初孕妇女会患上母体疟疾，随着妊娠状况的增加，对这种疾病的易感性降低，这表明妇女在连续怀孕期间会产生一定程度的保护性免疫。确定胎盘C4S与受寄生虫感染的红细胞(PRBC)相互作用的结构基序，了解受体-配体相互作用的细节，研究疟疾流行地区多胎妇女对C4S特异性寄生虫配体的免疫反应，以及对寄生虫配体的性质和结构的研究，可能有助于开发母体疟疾的治疗/疫苗。这项建议集中在C4S介导的PRBC与人胎盘硫酸软骨素蛋白多糖(CSPG)的黏附。我们的初步结果表明，胎盘CSPG的C4S链上的一个特定结构基序与PRBC结合，或者PRBC与胎盘CSPG的黏附可能涉及CSPG的核心蛋白/共纯化蛋白在最初的C4S特异性识别后的二次相互作用。初步研究还表明，特定的寡糖抑制PRBC与胎盘CSPG的黏附。该方案的总体目标是：(1)纯化人胎盘CSPG，并研究CSPG的糖胺多糖结构和与PRBC的结合特性。(2)确定CSPGs/共纯化蛋白的核心蛋白是否参与PRBC结合。(3)胎盘中结合PRBC的CSPG(S)的免疫荧光定位。(4)阐明支持PRBC黏附的C4S基序的最小尺寸和精细的结构特异性。(5)疟疾流行区多胎妊娠妇女C4S配体特异性免疫保护效果评价。这项研究的长期目标是：(A)了解为什么胎盘特别选择C4S结合恶性疟原虫；(B)研究胎盘中PRBC结合受体的表达；(C)确定PRBC上C4S结合配体的特征；(D)研究用于母体疟疾治疗的C4S寡糖或低聚糖模拟物；(E)开发用于母体疟疾治疗的C4S寡糖药物。

Recent studies suggest that during malaria infection in pregnant women, the placenta selects for a subpopulation of Plasmodium falcifarum by chondroitin 4-sulfate (C4S)-binding. In malaria endemic areas, primigravid women develop maternal malaria and susceptibility to the disease deceases as the gravid status increases, suggesting that women develop a level of protective immunity over successive pregnancies. Determination of the structural motif of the placental C4S that interacts with the parasite infected red blood cells (PRBCs), understanding of details of receptor-ligand interactions, studies on the immune response to C4S- specific parasite ligand in multigravid women living in malaria endemic areas, and studies on the nature and structure of the parasite ligand are likely to assist the development of therapy/vaccine for maternal malaria. This proposal focuses on C4S-mediated adherence of PRBCs to human placenta chondroitin sulfate proteoglycans (CSPG). Our preliminary results suggest that either a specific structural motif within the C4S chains of placental CSPGs binds PRBCs or the PRBC adherence to placenta CSPG may involve secondary interactions by either core proteins of CSPGs/co-purifying proteins after the initial C4S-specific recognition. Preliminary studies also show that specific oligosaccharides inhibit PRBC adherence to placenta CSPG. The overall goals of this proposal are to: (1) Purify human placental CSPGs, and study the glycosaminoglycan structures and PRBC binding characteristics of the CSPGs. (2) Determine whether the core proteins of CSPGs/co-purifying proteins participate in PRBC binding. (3) Immunofluorescence localization of PRBC- binding CSPG(s) in placenta. (4) Elucidation of the minimum size and fine structural specificity of the C4S motif that supports PRBCs adherence. (5) Evaluation of C4S ligand-specific immune protection in multigravid women living in malaria endemic areas. The long term goals of this study are to: (a) understand why placenta specifically selects for C4S-binding P. falciparum; (b) study the expression of the PRBC-binding receptor in placenta; (c) characterize the C4S- binding ligand on PRBCs; (d) study C4S oligosaccharides or oligosaccharide-mimetics for maternal malaria therapy; (e) develop C4S oligosaccharide-based drugs for maternal malaria therapy.