Binding properties determine the cytoadhesion of Plasmodium falciparum infected erythrocytes with the host

恶性疟原虫是造成人类疟疾相关发病和死亡的主要原因。恶性疟原虫感染的红细胞（IEs）粘附血管内皮的能力对疟疾的病理学具有重要意义。到目前为止，关于细胞粘附过程的动力学和动力学知之甚少。我们最近制定了细胞粘附过程的另一种模型。在该模型中，IEs通过内皮细胞受体（ECR） CD36从血液中移除（系缚），随后IEs以滚动方式移动。在稍后的时间点，由于内皮细胞（ECs）的刺激，与额外的ecr发生静态结合（粘附）。由该模型得出以下假设：PfEMP1蛋白通过滑动键与CD36结合；滚动表型导致ECs很少或没有激活。因此，结合有利于轻度疟疾的发展。2. PfEMP1蛋白通过catch结合与其他ecr结合，导致ECs的稳定结合和激活。因此，绑定有利于严重疟疾的发展。3. 即使在发热的情况下，IEs表面的旋钮对于粘附内皮也是必不可少的。因此，旋钮的形成有一种进化压力。4. VAR2CSA（与妊娠相关的疟疾有关）只能在胎盘中普遍存在低剪切力的情况下结合；因此，不会发生与其他器官内皮的结合。5. 基于结合表位序列的合成肽可以抑制ECs的激活。通过将转基因细胞与表达明确的ecr或pfemp1和1的疟原虫结合。原子力显微镜（AFM）（用于区分单结合和多结合以及滑移和捕获结合机制）与钙信号的测定相结合。表面声波生物传感器和等温滴定量热法（表征结合（结合和解离）），3。层流系统（表征结合表型）；AFM/电子和免疫荧光显微镜（可视化相互作用）；肽基抑制剂的合成（通过进化算法迭代改进），提出的假设将被研究。

Plasmodium falciparum is responsible for the majority of malaria related morbidity and mortality in humans. Of great importance for the pathology of malaria is the ability of P. falciparum infected erythrocytes (IEs) to cytoadhere to vascular endothelia. Until now, little is known concerning the kinetics and dynamics of the process of cytoadhesion. We have recently formulated an alternative model for the process of cytoadhesion. In this model, removal of IEs from the bloodstream (tethering) occurs via the endothelial cell receptor (ECR) CD36, over which IEs subsequently move in a rolling fashion. At a later time point, due to stimulation of endothelial cells (ECs), mostly static binding to additional ECRs takes place (adhesion). The following hypotheses result from this model: 1. PfEMP1 proteins bind to CD36 via a slip-bond; the rolling phenotype results in little or no activation of ECs. Therefore, binding favours the development of mild malaria. 2. PfEMP1 proteins bind to other ECRs via catch binding, resulting in stable binding and activation of ECs. Therefore, binding favours the development of severe malaria. 3. Knobs on the surface of IEs are essential to adhere to the endothelium even under febrile conditions. Thus, there is an evolutionary pressure on the formation of knobs. 4. VAR2CSA (responsible for pregnancy-associated malaria) can bind only in the presence of the low shear forces prevailing in the placenta; therefore, binding to the endothelium of other organs does not occur. 5. Synthetic peptides based on sequences of the binding epitopes can inhibit the activation of ECs. By combining transgenic cells and plasmodia expressing defined ECRs or PfEMP1s and 1. atomic force microscopy (AFM) (to distinguish between single and multiple bindings and between slip and catch binding mechanisms) in combination with the determination of calcium signalling, 2. surface acoustic wave biosensor and isothermal titration calorimetry (to characterise binding (association and dissociation), 3. laminar flow system (to characterise binding phenotype), 4. AFM/electron and immunofluorescence microscopy (to visualise interaction), and 5. synthesis of peptide-based inhibitors (iterative improvement by evolutionary algorithm), hypotheses raised will be investigated.