Surface co-expression of two different PfEMP1 antigens on single plasmodium falciparum-infected erythrocytes facilitates binding to ICAM1 and PECAM1.
Surface co-expression of two different PfEMP1 antigens on single plasmodium falciparum-infected erythrocytes facilitates binding to ICAM1 and PECAM1.
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DOI：
10.1371/journal.ppat.1001083
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发表时间：
2010-09-02
期刊：
影响因子：
6.7
通讯作者：
Jensen AT
中科院分区：
文献类型：
--
作者：
Joergensen L;Bengtsson DC;Bengtsson A;Ronander E;Berger SS;Turner L;Dalgaard MB;Cham GK;Victor ME;Lavstsen T;Theander TG;Arnot DE;Jensen AT
恶性疟原虫红细胞膜蛋白1 （PfEMP1）抗原在感染红细胞的细胞粘附（IE）、抗原变异和疟疾免疫中发挥重要作用。目前关于控制变异表面抗原表达的共识是，每个细胞一次只表达一个由一个var基因编码的PfEMP1。我们通过实时Q-PCR检测var mRNA转录物水平，通过单细胞FISH分析var基因转录物，并使用活共聚焦显微镜、流式细胞术和体外粘附实验直接将其与三种不同抗体选择的恶性疟原虫3D7亚系的PfEMP1抗原表面表达和细胞粘附进行比较。我们发现一个寄生虫亚系在单个IE上同时表达两种不同的var基因作为表面抗原。重要的是，这种寄生虫亚系可以结合CD31/PECAM1和CD54/ICAM1，并且与表面只有一个PfEMP1变体的感染细胞相比，其粘附在人内皮细胞上的效率是前者的两倍，这与粘附和疟疾发病机制的生理相关。这些关于PfEMP1抗原表达的新结果表明，需要重新评估恶性疟原虫粘附的分子机制和公认的绝对互斥var基因转录范式。恶性疟原虫是最具致病性的人类疟疾寄生虫，其毒性与其表达不同粘附蛋白的能力有关，这种粘附蛋白使发育中的被寄生红细胞能够与宿主的毛细血管结合，从而避免被脾脏清除。每个寄生虫大约有60个基因编码这种粘附蛋白的不同版本，这些蛋白的表面显示开关使寄生虫能够逃避免疫系统。在这里，我们发现这些结合蛋白的不同变体可以在单个感染的红细胞上同时表达，介导与不同内皮受体的结合。
The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens play a major role in cytoadhesion of infected erythrocytes (IE), antigenic variation, and immunity to malaria. The current consensus on control of variant surface antigen expression is that only one PfEMP1 encoded by one var gene is expressed per cell at a time. We measured var mRNA transcript levels by real-time Q-PCR, analysed var gene transcripts by single-cell FISH and directly compared these with PfEMP1 antigen surface expression and cytoadhesion in three different antibody-selected P. falciparum 3D7 sub-lines using live confocal microscopy, flow cytometry and in vitro adhesion assays. We found that one selected parasite sub-line simultaneously expressed two different var genes as surface antigens, on single IE. Importantly, and of physiological relevance to adhesion and malaria pathogenesis, this parasite sub-line was found to bind both CD31/PECAM1 and CD54/ICAM1 and to adhere twice as efficiently to human endothelial cells, compared to infected cells having only one PfEMP1 variant on the surface. These new results on PfEMP1 antigen expression indicate that a re-evaluation of the molecular mechanisms involved in P. falciparum adhesion and of the accepted paradigm of absolutely mutually exclusive var gene transcription is required. Plasmodium falciparum is the most pathogenic human malaria parasite and its virulence has been linked to its capacity to express different adhesion proteins that enable the developing parasitized erythrocyte to bind to capillaries of the host, thereby avoiding removal by the spleen. Each parasite has approximately 60 genes encoding different versions of this adhesion protein, and a switch in surface display of these proteins enables the parasite to evade the immune system. Here we show that different variants of these binding proteins can be found expressed simultaneously on single infected red blood cells mediating binding to different endothelial receptors.
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