Structural requirements for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate proteoglycans of human placenta
Structural requirements for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate proteoglycans of human placenta
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DOI：
10.1074/jbc.m006399200
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发表时间：
2000-12-22
影响因子：
4.8
通讯作者：
Gowda, DC
中科院分区：
文献类型：
--
作者：
Alkhalil, A;Achur, RN;Gowda, DC
妊娠期间恶性疟原虫感染会导致受感染的红细胞（IRBC）在胎盘中积聚，导致妊娠结局不佳。在前一篇论文（Achur，R.N.，Valiyaveettil，M.，Alkhalil，A.，奥肯豪斯角F.、和Gowda，D.C.（2000）J.Biol.Chem.275，40344-40356），我们报道了胎盘绒毛间隙中异常低的硫酸化硫酸软骨素蛋白聚糖（CSPG）介导IRBC粘附。在这项研究中，我们报告的结构要求的粘附和最低的软骨素4-硫酸（C4 S）的结构基序，支持IRBC的粘附。通过完全硫酸化的C4 S的溶剂解酯化制备具有不同硫酸根含量的部分硫酸化的C4 S。这些和其他未修饰的C4 S，与不同比例的4-，6-，和非硫酸化二糖重复，进行了分析，抑制IRBC粘附胎盘CSPG。含有30- 50%4-硫酸化和50-70%非硫酸化二糖重复的C4 S有效地抑制IRBC粘附; C6 S没有抑制活性。通过含有不同水平的4-硫酸化的C4 Ss的部分解聚制备不同尺寸的寡聚体，并研究其抑制IRBC粘附的能力。具有六个或更多个二糖重复的寡聚体抑制IRBC粘附至与完整C4 Ss相同的水平，表明十二糖是最佳IRBC粘附所需的最小结构基序。在C4 S十二糖中，只有那些每个分子具有两个或三个硫酸基团的十二糖显示出最大的IRBC抑制。这些数据定义了IRBC粘附胎盘CSPG的结构要求，并对母体疟疾治疗药物的开发产生影响。
Plasmodium falciparum infection during pregnancy results in the accumulation of infected red blood cells (IRBCs) in the placenta, leading to poor pregnancy outcome. In the preceding paper (Achur, R.N., Valiyaveettil, M., Alkhalil, A., Ockenhouse, C. F., and Gowda, D.C. (2000) J. Biol. Chem. 275, 40344-40356), we reported that unusually low sulfated chondroitin sulfate proteoglycans (CSPGs) in the intervillous spaces of the placenta mediate the IRBC adherence. In this study, we report the structural requirements for the adherence and the minimum chondroitin 4-sulfate (C4S) structural motif that supports IRBC adherence. Partially sulfated C4Ss with varying sulfate contents were prepared by solvolytic desulfation of a fully sulfated C4S. These and other nonmodified C4Ss, with different proportions of 4-, 6-, and nonsulfated disaccharide repeats, were analyzed for inhibition of IRBC adherence to the placental CSPG. C4Ss containing 30-50% 4-sulfated and 50-70% nonsulfated disaccharide repeats efficiently inhibited IRBC adherence; C6S had no inhibitory activity. Oligosaccharides of varying sizes were prepared by the partial depolymerization of C4Ss containing varying levels of 4-sulfation, and their ability to inhibit the IRBC adherence was studied. Oligosaccharides with six or more disaccharide repeats inhibited IRBC adherence to the same level as that of the intact C4Ss, indicating that a dodecasaccharide is the minimum structural motif required for optimal IRBC adherence. Of the C4S dodecasaccharides, only those with two or three sulfate groups per molecule showed maximum IRBC inhibition. These data define the structural requirements for the IRBC adherence to placental CSPGs with implications for the development of therapeutics for maternal malaria.