Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion
Plasmodium falciparum erythrocyte-binding antigen 175 triggers a biophysical change in the red blood cell that facilitates invasion
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DOI：
10.1073/pnas.1620843114
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发表时间：
2017-04-18
影响因子：
11.1
通讯作者：
Baum, Jake
中科院分区：
文献类型：
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作者：
Koch, Marion;Wright, Katherine E.;Baum, Jake
疟原虫侵入红细胞(RBC)定义了疟疾发病机制的开始。到目前为止，对侵袭性的实验研究主要集中在寄生虫粘附素或信号通路的作用以及红细胞表面结合受体的身份。红细胞内的信号通路可能会改变红细胞的生物物理性质以促进侵袭，但其潜在作用在很大程度上被忽视了。寄生虫红细胞结合抗原175(EBA175)是大多数寄生虫株进入红细胞所必需的一种蛋白质，它通过与红细胞表面的糖蛋白A(GPA)结合而发挥关键作用，尽管这种结合作用的功能尚不清楚。在这里，使用实时变形性细胞仪和闪烁光谱来定义红细胞的生物物理性质，我们表明EBA175与GPA结合导致红细胞细胞骨架张力增加和细胞膜弯曲模数降低。我们分离了细胞骨架和细胞膜的变化，并表明弯曲模数的降低与寄生虫的入侵效率直接相关。这些数据强烈表明，疟疾寄生虫通过其结合抗原启动红细胞表面，改变目标细胞的生物物理性质，从而减少入侵的关键能量屏障。这一发现将是我们对疟疾寄生虫入侵概念的重大改变，表明事实上，这是寄生虫和宿主细胞物理力量共同作用以促进入侵之间的平衡。
Invasion of the red blood cell (RBC) by the Plasmodium parasite defines the start of malaria disease pathogenesis. To date, experimental investigations into invasion have focused predominantly on the role of parasite adhesins or signaling pathways and the identity of binding receptors on the red cell surface. A potential role for signaling pathways within the erythrocyte, which might alter red cell biophysical properties to facilitate invasion, has largely been ignored. The parasite erythrocyte-binding antigen 175 (EBA175), a protein required for entry in most parasite strains, plays a key role by binding to glycophorin A (GPA) on the red cell surface, although the function of this binding interaction is unknown. Here, using real-time deformability cytometry and flicker spectroscopy to define biophysical properties of the erythrocyte, we show that EBA175 binding to GPA leads to an increase in the cytoskeletal tension of the red cell and a reduction in the bending modulus of the cell's membrane. We isolate the changes in the cytoskeleton and membrane and show that reduction in the bending modulus is directly correlated with parasite invasion efficiency. These data strongly imply that the malaria parasite primes the erythrocyte surface through its binding antigens, altering the biophysical nature of the target cell and thus reducing a critical energy barrier to invasion. This finding would constitute a major change in our concept of malaria parasite invasion, suggesting it is, in fact, a balance between parasite and host cell physical forces working together to facilitate entry.