CYTOADHERENCE IN MATERNAL MALARIA

母体疟疾中的细胞粘附

• 批准号: 6510968
• 负责人: CHANNE D GOWDA
• 金额: $ 21.9万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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/6510968
• 关键词: Plasmodium falciparum; SDS polyacrylamide gel electrophoresis; antibody formation; antibody specificity; cell adhesion; cellular immunity; cellular pathology; chondroitin sulfates; clinical research; 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（C4 S）结合选择恶性疟原虫亚群。 在疟疾流行地区，怀孕后的妇女会患上孕产妇疟疾，随着怀孕状况的增加，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。 确定胎盘C4 S与寄生虫感染的红细胞（PRBCs）相互作用的结构基序，了解受体-配体相互作用的细节，研究对疟疾流行区多次妊娠妇女中C4 S特异性寄生虫配体的免疫应答，以及研究寄生虫配体的性质和结构可能有助于开发母体疟疾的治疗/疫苗。该提案的重点是C4 S介导的PRBCs粘附到人胎盘硫酸软骨素蛋白聚糖（CSPG）。 我们的初步结果表明，无论是一个特定的结构基序内的C4 S链的胎盘CSPG结合PRBC或PRBC粘附胎盘CSPG可能涉及二次相互作用的CSPG的核心蛋白/共纯化蛋白后，最初的C4 S特异性识别。 初步研究还表明，特定的寡糖抑制PRBC粘附胎盘CSPG。本研究的主要目的是：（1）纯化人胎盘CSPG，并研究其糖胺聚糖结构和PRBC结合特性。 (2)确定CSPG/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)支持PRBC粘附的C4 S基序的最小尺寸和精细结构特异性的阐明。 (5)疟疾流行区经产妇女C4 S配体特异性免疫保护的评价本研究的长期目标是：（a）了解为什么胎盘特异性选择C4 S结合恶性疟原虫;（B）研究胎盘中PRBC结合受体的表达;（c）表征PRBC上的C4 S结合配体;（d）研究用于母体疟疾治疗的C4 S寡糖或寡糖模拟物;（e）开发用于母体疟疾治疗的基于C4 S寡糖的药物。