Characterisation of Plasmodium falciparum populations selected on the human endothelial receptors P-selectin, E-selectin, CD9 and CD151

Abstract

The ability of the parasite Plasmodium falciparum to evade the immune system and be sequestered within human small blood vessels is responsible for severe forms of malaria. The sequestration depends on the interaction between human endothelial receptors and P. falciparum erythrocyte membrane protein 1 (PfEMP1) exposed on the surface of the infected erythrocytes (IEs). In this study, the transcriptomes of parasite populations enriched for parasites that bind to human P-selectin, E-selectin, CD9 and CD151 receptors were analysed. IT4_var02 and IT4_var07 were specifically expressed in IT4 parasite populations enriched for P-selectin-binding parasites; eight var genes (IT4_var02/07/09/13/17/41/44/64) were specifically expressed in isolate populations enriched for CD9-binding parasites. Interestingly, IT4 parasite populations enriched for E-selectin- and CD151-binding parasites showed identical expression profiles to those of a parasite population exposed to wild-type CHO-745 cells. The same phenomenon was observed for the 3D7 isolate population enriched for binding to P-selectin, E-selectin, CD9 and CD151. This implies that the corresponding ligands for these receptors have either weak binding capacity or do not exist on the IE surface. Conclusively, this work expanded our understanding of P. falciparum adhesive interactions, through the identification of var transcripts that are enriched within the selected parasite populations.

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

“…That we did not find significant differences in receptor usage between the UM and CM isolates could be explained by the infection consisting of multiple P. falciparum genotypes, including those underlying var gene expression (Montgomery et al, 2006(Montgomery et al, , 2007. It is clear that HBMEC binding of some isolates is not affected by inhibition with aICAM-1 and rEPCR, indicating that other receptors may play a role in cytoadherence to brain endothelium, a phenomenon also seen with selected laboratory strains (Yipp et al, 2007;Avril et al, 2016;Mahamar et al, 2017;Metwally et al, 2017). Lately, dual receptor binding by one PfEMP1 variant has been reported, with some PfEMP1 being able to bind both EPCR and ICAM or CD36 and ICAM-1 simultaneously Lennartz et al, 2017).…”

“…We also determined binding of the patient isolates to HBMEC and HDMEC in the presence of aICAM-1 antibody and rEPCR combined, but the limited data (Appendix Fig S3) showed no significant difference between UM and CM isolates, nor between HBMEC and HDMEC binding. It is clear that HBMEC binding of some isolates is not affected by inhibition with aICAM-1 and rEPCR, indicating that other receptors may play a role in cytoadherence to brain endothelium, a phenomenon also seen with selected laboratory strains (Yipp et al, 2007;Avril et al, 2016;Mahamar et al, 2017;Metwally et al, 2017).…”

Adhesion between P. falciparum infected erythrocytes and human endothelial receptors follows alternative binding dynamics under flow and febrile conditions

“…Finally, adherent IEs are counted manually. These experiments demonstrated that laboratory-adapted trophozoite-stage IT4 and 3D7 isolates show different binding capacities to various ECRs under static conditions 31,33 . The main objective of this study was to characterize the binding behavior of erythrocytes infected with P. falciparum to the ECRs CD36, ICAM-1, P-selectin, CD9, and CSA under controlled flow and temperature conditions.…”

“…Endothelial cytoadhesion and the binding capacities of various laboratory strains and patient isolates of P. falciparum have been mainly investigated under static conditions 6,31,32 . This is classically achieved by directly incubating IEs with cells or recombinant receptors of interest 8,16,33,34 . Finally, adherent IEs are counted manually.…”

“…The main objective of this study was to characterize the binding behavior of erythrocytes infected with P. falciparum to the ECRs CD36, ICAM-1, P-selectin, CD9, and CSA under controlled flow and temperature conditions. For this purpose, we used transfected CHO cells expressing GFP fusions of the receptors of interest on the cell surface 33 . P. falciparum populations with increased binding for ICAM-1, P-selectin and CD9 receptors were obtained by performing at least seven rounds of enrichment, as described previously 33 .…”