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

结合特性决定了恶性疟原虫感染的红细胞与宿主的细胞粘附

• 批准号: 491917256
• 负责人: Professorin Dr. Iris Bruchhaus
• 金额: --
• 依托单位: Bernhard-Nocht-Institut für Tropenmedizin (BNITM)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/491917256?language=en
• 关键词: Binding; properties; determine; cytoadhesion; Plasmodium

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.

恶性疟原虫是造成人类中大多数疟疾相关发病率和死亡率的原因。恶性疟原虫感染的红细胞（IE）粘附于血管内皮细胞的能力对疟疾的病理学非常重要。到目前为止，对细胞粘附过程的动力学和动力学知之甚少。我们最近制定了一个替代模型的过程中的细胞粘附。在该模型中，通过内皮细胞受体（ECR）CD 36从血流中去除IE（栓系），随后IE以滚动方式在其上移动。在稍后的时间点，由于内皮细胞（EC）的刺激，发生与另外的ECR的大部分静态结合（粘附）。本模型得出以下假设：1. PfEMP 1蛋白通过滑动键与CD 36结合;滚动表型导致EC很少或没有激活。因此，结合有利于轻度疟疾的发展。2. PfEMP 1蛋白通过捕获结合与其他ECR结合，导致EC的稳定结合和激活。因此，捆绑有利于严重疟疾的发展。3.即使在发热条件下，IE表面上的旋钮也是粘附于内皮的必要条件。因此，有一个进化的压力形成的旋钮。4. VAR 2CSA（负责妊娠相关疟疾）只能在胎盘中普遍存在低剪切力的情况下结合;因此，不会与其他器官的内皮结合。5.基于结合表位序列的合成肽可以抑制EC的活化。通过组合转基因细胞和表达确定的ECR或PfEMP 1和1的疟原虫。原子力显微镜（AFM）（以区分单一和多重结合以及滑动和捕获结合机制）结合钙信号传导的测定，2.表面声波生物传感器和等温滴定量热法（对结合（缔合和解离），3.层流系统（对β-内酰胺酶结合表型），4. AFM/电子和免疫荧光显微镜（可视化相互作用），和5。基于肽的抑制剂的合成（通过进化算法的迭代改进），将研究提出的假设。