Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, Copenhagen University Hospital (Rigshospitalet), University of Copenhagen, Copenhagen, Denmark.
PLoS One. 2013 Jul 9;8(7):e69117. doi: 10.1371/journal.pone.0069117. Print 2013.
Members of the Plasmodium falciparum Erythrocyte Membrane protein 1 (PfEMP1) family expressed on the surface of malaria-infected erythrocytes mediate binding of the parasite to different receptors on the vascular lining. This process drives pathologies, and severe childhood malaria has been associated with the expression of particular subsets of PfEMP1 molecules. PfEMP1 are grouped into subtypes based on upstream sequences and the presence of semi-conserved PfEMP1 domain compositions named domain cassettes (DCs). Earlier studies have indicated that DC5-containing PfEMP1 (DC5-PfEMP1) are more likely to be expressed in children with severe malaria disease than in children with uncomplicated malaria, but these PfEMP1 subtypes only dominate in a relatively small proportion of the children with severe disease. In this study, we have characterised the genomic sequence characteristic for DC5, and show that two genetically different parasite lines expressing DC5-PfEMP1 bind PECAM1, and that anti-DC5-specific antibodies inhibit binding of DC5-PfEMP1-expressing parasites to transformed human bone marrow endothelial cells (TrHBMEC). We also show that antibodies against each of the four domains characteristic for DC5 react with native PfEMP1 expressed on the surface of infected erythrocytes, and that some of these antibodies are cross-reactive between the two DC5-containing PfEMP1 molecules tested. Finally, we confirm that anti-DC5 antibodies are acquired early in life by individuals living in malaria endemic areas, that individuals having high levels of these antibodies are less likely to develop febrile malaria episodes and that the antibody levels correlate positively with hemoglobin levels.
疟原虫红细胞膜蛋白 1（PfEMP1）家族成员在疟原虫感染的红细胞表面表达，介导寄生虫与血管内皮上不同受体的结合。这个过程驱动了病理学的发生，严重的儿童疟疾与特定 PfEMP1 分子亚群的表达有关。PfEMP1 根据上游序列和存在半保守 PfEMP1 结构域组成（称为结构域盒（DC））进行分组。早期研究表明，含有 DC5 的 PfEMP1（DC5-PfEMP1）比无并发症疟疾儿童更有可能在严重疟疾儿童中表达，但这些 PfEMP1 亚型仅在相对较小比例的严重疾病儿童中占主导地位。在这项研究中，我们对 DC5 的基因组序列特征进行了表征，表明两种表达 DC5-PfEMP1 的遗传上不同的寄生虫系结合 PECAM1，并且抗 DC5 特异性抗体抑制表达 DC5-PfEMP1 的寄生虫与转化的人骨髓内皮细胞（TrHBMEC）的结合。我们还表明，针对 DC5 四个特征结构域中的每一个的抗体与感染红细胞表面表达的天然 PfEMP1 反应，并且这些抗体中的一些在测试的两种含有 DC5 的 PfEMP1 分子之间具有交叉反应性。最后，我们证实抗 DC5 抗体是在疟疾流行地区生活的个体在生命早期获得的，具有这些抗体高水平的个体不太可能发生发热性疟疾发作，并且抗体水平与血红蛋白水平呈正相关。
