Human erythrocyte band 3 is a host receptor for Plasmodium falciparum glutamic acid-rich protein
Human erythrocyte band 3 is a host receptor for Plasmodium falciparum glutamic acid-rich protein
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DOI：
10.1182/blood-2018-07-865451
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发表时间：
2019-01-31
期刊：
影响因子：
20.3
通讯作者：
Chishti, Athar H.
中科院分区：
文献类型：
--
作者：
Almukadi, Haifa;Schwake, Christopher;Chishti, Athar H.
疟疾仍然是对人类健康和经济发展的一个重大全球威胁。由恶性疟原虫感染的人红细胞/红细胞引起的微血管病变是导致高死亡率的严重发病机制的标志，特别是在撒哈拉以南非洲的儿童中。在这项研究中，我们使用了噬菌体展示互补DNA文库筛选策略，以确定恶性疟原虫谷氨酸丰富蛋白（PfGARP）作为分泌的配体，识别人红细胞阴离子交换剂，带3/AE 1，作为宿主受体的胞外域。PfGARP的结构域定位揭示了编码免疫应答表位和核心红细胞结合活性的不同非重叠重复序列。从PfGARP的红细胞结合重复序列衍生的合成肽诱导红细胞聚集，使人联想到玫瑰花结现象。使用源自免疫原性重复序列的肽，开发了定量免疫测定法来检测从马里农村患者获得的人血浆样品中针对PfGARP的选择性免疫应答，表明PfGARP作为疾病进展的潜在生物标志物的可行性。总的来说，我们的研究结果表明，PfGARP可能发挥功能作用，通过结合带3作为宿主受体，增强人红细胞的粘附特性。我们提出PfGARP的免疫学和药理学抑制可能揭示减轻脑和妊娠相关疟疾病变的新治疗选择。
Malaria remains a major global threat to human health and economic development. Microvascular lesions caused by Plasmodium falciparum-infected human erythrocytes/red blood cells are hallmarks of severe pathogenesis contributing to highmortality, particularly in children fromsub-Saharan Africa. In this study, we used a phage display complementaryDNA library screening strategy to identify P falciparum glutamic acid-rich protein (PfGARP) as a secreted ligand that recognizes an ectodomain of human erythrocyte anion-exchanger, band 3/AE1, as a host receptor. Domain mapping of PfGARP revealed distinct non-overlapping repeats encoding the immune response epitopes and core erythrocyte-binding activity. Synthetic peptides derived from the erythrocyte-binding repeats of PfGARP induced erythrocyte aggregation reminiscent of the rosetting phenomenon. Using peptides derived from the immunogenic repeats, a quantitative immunoassay was developed to detect a selective immune response against PfGARP in human plasma samples obtained from patients in rural Mali, suggesting the feasibility of PfGARP as a potential biomarker of disease progression. Collectively, our results suggest that PfGARP may play a functional role in enhancing the adhesive properties of human erythrocytes by engaging band 3 as a host receptor. We propose that immunological and pharmacological inhibition of PfGARP may unveil new therapeutic options for mitigating lesions in cerebral and pregnancy-associated malaria.