CYTOADHERENCE IN MATERNAL MALARIA

母体疟疾中的细胞粘附

• 批准号: 6170693
• 负责人: CHANNE D GOWDA
• 金额: $ 22.93万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170693
• 关键词: Plasmodium falciparum; SDS polyacrylamide gel electrophoresis; antibody formation; antibody specificity; cell adhesion; cellular immunity; cellular pathology; chondroitin sulfates; density gradient ultracentrifugation; electrospray ionization mass spectrometry; enzyme linked immunosorbent assay; erythrocytes; fast atom bombardment mass spectrometry; gas chromatography mass spectrometry; gel filtration chromatography; human tissue; immunofluorescence technique; ion exchange chromatography; laboratory rabbit; malaria; matrix assisted laser desorption ionization; molecular shape; placenta; proteoglycan; receptor binding; receptor expression

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.

最近的研究表明，在孕妇感染疟疾期间，胎盘通过 4-硫酸软骨素 (C4S) 结合来选择恶性疟原虫亚群。 在疟疾流行地区，初产妇会患上母体疟疾，并且随着妊娠状况的增加，对这种疾病的易感性也会降低，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力。 确定与寄生虫感染的红细胞 (PRBC) 相互作用的胎盘 C4S 的结构基序，了解受体-配体相互作用的细节，研究生活在疟疾流行地区的多妊娠妇女对 C4S 特异性寄生虫配体的免疫反应，对寄生虫配体的性质和结构的研究可能有助于母体疟疾治疗/疫苗的开发。该提案的重点是 C4S 介导的 PRBC 与人胎盘硫酸软骨素蛋白聚糖 (CSPG) 的粘附。 我们的初步结果表明，胎盘 CSPG 的 C4S 链内的特定结构基序结合 PRBC，或者 PRBC 粘附到胎盘 CSPG 可能涉及在初始 C4S 特异性识别后 CSPG 核心蛋白/共纯化蛋白的二次相互作用。 初步研究还表明，特定的寡糖可抑制 PRBC 与胎盘 CSPG 的粘附。该提案的总体目标是：（1）纯化人胎盘CSPG，并研究CSPG的糖胺聚糖结构和PRBC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PRBC结合CSPG的免疫荧光定位。 (4) 阐明支持 PRBC 粘附的 C4S 基序的最小尺寸和精细结构特异性。 (5)疟疾流行地区多妊娠妇女C4S配体特异性免疫保护的评价。本研究的长期目标是： (a) 了解为什么胎盘专门选择结合 C4S 的恶性疟原虫； (b) 研究胎盘中 PRBC 结合受体的表达； (c) 表征 PRBC 上的 C4S 结合配体； (d) 研究 C4S 寡糖或寡糖模拟物用于孕产妇疟疾治疗； (e) 开发用于母体疟疾治疗的 C4S 寡糖药物。