characterizing the adhesive dynamics of Plasmodium falciparum infected erythrocytes (IEs) to different endothelial cell receptors (ECRs) in flow is a big challenge considering available methods. This study investigated the adhesive dynamics of IEs to five ECRs (CD36, ICAM-1, P-selectin, CD9, CSA) using simulations of in vivo-like flow and febrile conditions. To characterize the interactions between ECRs and knobby and knobless IEs of two laboratory-adapted P. falciplarum isolates, cytoadhesion analysis over time was performed using a new tracking bioinformatics method. The results revealed that IEs performed rolling adhesion exclusively over CD36, but exhibited stationary binding to the other four ECRs. The absence of knobs affected rolling adhesion both with respect to the distance travelled by IEs and their velocity. Knobs played a critical role at febrile temperatures by stabilizing the binding interaction. Our results clearly underline the complexity of the IE-receptor interaction and the importance of knobs for the survival of the parasite at fever temperatures, and lead us to propose a new hypothesis that could open up new strategies for the treatment of malaria. Cytoadhesion of Plasmodium falciparum to human endothelial cell receptors (ECRs) causes complications and deaths following malaria infection. In 2018, 405,000 malaria-related deaths were registered (61% of which were of children younger than 5 years old) 1. Cytoadhesion leads to accumulation of infected erythrocytes (IEs) within the microvascular bed of vital organs such as the brain, lungs, and kidneys. Death can eventually occur due to decreased blood supply and organ failure 2,3. Cytoadhesion results from interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and different ECRs 4-8. About 60 var genes per parasite genome encode PfEMP1 family members. Only one PfEMP1 variant is located on the membrane of IEs at the trophozoite stage, but the corresponding var gene is already expressed at the ring stage in a mutually exclusive pattern 9. The most studied interaction partners are the ECRs CD36, intracellular adhesion molecule 1 (ICAM-1), endothelial protein C receptor, and chondroitin sulfate A (CSA) 6,7. In general, PfEMP1 molecules cluster on nanoscale protrusions, called knobs, located on the membrane of IEs. Knobs consist of various submembranous structural proteins, predominantly knob-associated histidine-rich protein (KAHRP) 10. KAHRP contains several binding domains that interact with both parasite and host factors. Knobs begin to appear on the surface of IEs at 16 h post-invasion (hpi). The density of knobs increases from 20 to 60/µm 2 with parasite development from the
Changes in the erythrocyte membrane induced by Plasmodium falciparum invasion allow cytoadhesion of infected erythrocytes (IEs) to the host endothelium, which can lead to severe complications. Binding to endothelial cell receptors (ECRs) is mainly mediated by members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by var genes. Malaria infection causes several common symptoms, with fever being the most apparent. In this study, the effects of febrile conditions on cytoadhesion of predominately knobless erythrocytes infected with the laboratory isolate IT4 to chondroitin-4-sulfate A (CSA), intercellular adhesion molecule 1 (ICAM-1), and CD36 were investigated. IEs enriched for binding to CSA at 40 °C exhibited significantly increased binding capacity relative to parasites enriched at 37 °C. This interaction was due to increased var2csa expression and trafficking of the corresponding PfEMP1 to the IE surface as well as to a selection of knobby IEs. Furthermore, the enrichment of IEs to ICAM-1 at 40 °C also led to selection of knobby IEs over knobless IEs, whereas enrichment on CD36 did not lead to a selection. In summary, these findings demonstrate that knobs are crucial for parasitic survival in the host, especially during fever episodes, and thus, that selection pressure on the formation of knobs could be controlled by the host.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.