Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria.
Cytoadhesion to gC1qR through Plasmodium falciparum Erythrocyte Membrane Protein 1 in Severe Malaria.
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DOI：
10.1371/journal.ppat.1006011
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发表时间：
2016-11
期刊：
影响因子：
6.7
通讯作者：
Mayor A
中科院分区：
文献类型：
--
作者：
Magallón-Tejada A;Machevo S;Cisteró P;Lavstsen T;Aide P;Rubio M;Jiménez A;Turner L;Valmaseda A;Gupta H;De Las Salas B;Mandomando I;Wang CW;Petersen JE;Muñoz J;Gascón J;Macete E;Alonso PL;Chitnis CE;Bassat Q;Mayor A
恶性疟原虫感染的红细胞对 gC1qR 的细胞粘附与严重疟疾有关，但目前尚不清楚所涉及的寄生虫配体。为了评估与 gC1qR 的结合是否是通过恶性疟原虫红细胞膜蛋白 1 (PfEMP1) 家族介导的，我们通过静态结合测定和 qPCR 分析了来自患有严重和单纯性疟疾的莫桑比克儿童的 86 株恶性疟原虫分离株以及选择用于结合的恶性疟原虫 3D7 品系的细胞粘附和 var 基因转录谱。 gC1qR (Pf3D7gC1qR)。 DC8 的转录水平与 gC1qR 的细胞粘附呈正相关（rho = 0.287，P = 0.007），在严重贫血儿童的分离株中高于无并发症的疟疾，在首次疟疾发作的欧洲人（n = 21）中的分离株高于莫桑比克成年人（n = 25），并且与感染红细胞的 IgG 识别增加相关通过流式细胞术。与未选择的品系（0.001倍）相比，Pf3D7gC1qR过表达DC8型PFD0020c（相对于丝氨酰-tRNA合成酶基因的5.3倍转录水平）。在基于 ELISA 的结合测定中，来自 PFD0020c 的 DBLβ12 与 gC1qR 结合，针对该结构域的多克隆抗体能够将 Pf3D7gC1qR 和四种莫桑比克恶性疟原虫分离株与 gC1qR 的结合抑制 50%。我们的结果表明，DC8 型 PfEMP1 通过 DBLβ12 结构域中的保守表面表位介导与 gC1qR 的结合，该表位可被菌株超越功能抗体抑制。这项研究支持 gC1qR 在疟疾相关血管内发病机制中的关键作用，并表明针对这种特定相互作用设计针对严重疟疾的干预措施的可行性。 恶性疟原虫隔离在重要器官中。这种现象是由受感染的红细胞与微脉管系统中的宿主受体的细胞粘附介导的，导致了严重疟疾的发展。尽管内皮蛋白 C 受体的细胞粘附在严重疟疾中起核心作用，但其他宿主受体也可能参与其中。我们通过对莫桑比克患者和实验室寄生虫株的恶性疟原虫分离株进行分析得出的结果表明，DC8 型 PfEMP1 的特定结构域 (DBLβ12) 可以与人类受体 gC1qR 结合，该受体先前与严重疟疾相关。我们的研究结果表明，针对 PfEMP1 的抗体可以对 gC1qR 结合提供超越菌株的抑制。总体而言，这些结果支持 gC1qR 粘附在疟疾相关血管内发病机制中的关键作用，以及针对这种特定相互作用的新干预措施的可行性。
Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased IgG recognition of infected erythrocytes by flow cytometry. Pf3D7gC1qR overexpressed the DC8 type PFD0020c (5.3-fold transcript levels relative to Seryl-tRNA-synthetase gene) compared to the unselected line (0.001-fold). DBLβ12 from PFD0020c bound to gC1qR in ELISA-based binding assays and polyclonal antibodies against this domain were able to inhibit binding to gC1qR of Pf3D7gC1qR and four Mozambican P. falciparum isolates by 50%. Our results show that DC8-type PfEMP1s mediate binding to gC1qR through conserved surface epitopes in DBLβ12 domain which can be inhibited by strain-transcending functional antibodies. This study supports a key role for gC1qR in malaria-associated endovascular pathogenesis and suggests the feasibility of designing interventions against severe malaria targeting this specific interaction. Plasmodium falciparum sequesters in vital organs. This phenomenon mediated by cytoadhesion of infected-erythrocytes to host receptors in the microvasculature, contributes to the development of severe malaria. Although cytoadhesion to Endothelial Protein-C Receptor has a central role in severe malaria, other host receptors are also likely to be involved. Our results generated by the analysis of P. falciparum isolates from Mozambican patients and laboratory parasite lines indicate that a specific domain (DBLβ12) from DC8-type PfEMP1s can bind to the human receptor gC1qR, previously associated with severe malaria. Our findings revealed that antibodies against PfEMP1 could provide strain-transcending inhibition of gC1qR-binding. Overall, these results support a key role for the adhesion to gC1qR in malaria-associated endovascular pathogenesis and the feasibility of new interventions targeting this specific interaction.
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