Project Details
Projekt
Binding properties determine the cytoadhesion of Plasmodium falciparum infected erythrocytes with the host
Subject Area
Parasitology and Biology of Tropical Infectious Disease Pathogens
Biophysics
Biophysics
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 491917256
A key factor in the pathology of the human malaria parasite Plasmodium falciparum is its ability to adhere infected red blood cells (iRBCs) to endothelial cell receptors (ECRs) which leads to capillary blockage, cytokine release, and endothelial dysfunction. Cytoadhesion is mediated by PfEMP1 molecules, presented in knobs on iRBC surfaces. Although progress has been made in understanding the interactions between iRBCs and ECRs, many questions still need to be answered. In order to fill this gap, we carried out appropriate expressions and obtained the following results: (i) The utility of the selection-linked integration (SLI) method in producing parasites expressing specific PfEMP1 variants on iRBCs, enabling focused study of host-parasite interactions. (ii) Single-cell force spectroscopy is utilized to discern distinct binding behaviors between SLIvar-iRBCs and various ECRs. (iii) Enhanced expression of genes encoding cytokine and antiviral proteins in brain endothelial cells (ECs) upon interaction with the iRBCs. (iv) Altered expression profiles of primary brain and lung ECs under shear stress and incubation with ring-stage iRBCs. (v) Successful inhibition of binding using synthetic peptides mimicking CD36 and ICAM-1 structures. Based on the results, the following hypothesis will be tested: Variations in EC origin, shear stress, temperature, and PfEMP1 variant presented will result in different responses of ECs to cytoadhesion of iRBCs and thus have implications on the severity of the disease. The key objectives include: 1. Determining the shear force threshold for iRBC-ECR binding initiation, conditions leading to binding destabilization, and the dynamics and velocity of iRBC movement during this process. 2. Determine the binding of SLIvar-iRBCs to ECs derived from different organs, investigate the influence of TNF stimulation and febrile temperatures on the cytoadhesion effects and on the expression of ECs, and characterize the types of binding according to point 1. 3. Quantifying forces within identified interactions and assessing their dependency on knob density, dimensions, and PfEMP1 molecule quantities. 4. The synthetic 20-mer peptides, identified for their ability to impede cytoadhesion to CD36 and ICAM-1, should serve as a foundational platform for enhancing inhibitor efficacy through iterative development cycles. State-of-the-art technology (like laminar flow system, atomic force microscopy, ultrastructure expansion microscopy, and cryo-electron microscopy), should be used to reach these goals. Through these investigations, we aim to unveil crucial insights into the mechanics and implications of iRBC-EC interactions, potentially paving the way for targeted interventions against severe malaria manifestations.
DFG Programme
Priority Programmes
Subproject of
SPP 2332:
Physics of Parasitism
