In vitro inhibition and reversal of Plasmodium falciparum cytoadherence to endothelium by monoclonal antibodies to ICAM-1 and CD36

Abstract

BackgroundSequestration of parasitized red blood cells from the peripheral circulation during an infection with Plasmodium falciparum is caused by an interaction between the parasite protein PfEMP1 and receptors on the surface of host endothelial cells, known as cytoadherence. Several lines of evidence point to a link between the pathology of severe malaria and cytoadherence, therefore blocking adhesion receptors involved in this process could be a good target to inhibit pRBC sequestration and prevent disease. In a malaria endemic setting this is likely to be used as an adjunct therapy by reversing existing cytoadherence. Two well-characterized parasite lines plus three recently derived patient isolates were tested for their cytoadherence to purified receptors (CD36 and ICAM-1) as well as endothelial cells. Monoclonal antibodies against human CD36 and ICAM-1 were used to inhibit and reverse infected erythrocyte binding in static and flow-based adhesion assays.ResultsAnti-ICAM-1 and CD36 monoclonal antibodies were able to inhibit and reverse P. falciparum binding of lab and recently adapted patient isolates in vitro. However, reversal of binding was incomplete and varied in its efficiency between parasite isolates.ConclusionsThe results show that, as a proof of concept, disturbing existing ligand–receptor interactions is possible and could have potential therapeutic value for severe malaria. The variation seen in the degree of reversing existing binding with different parasite isolates and the incomplete nature of reversal, despite the use of high affinity inhibitors, suggest that anti-adhesion approaches as adjunct therapies for severe malaria may not be effective, and the focus may need to be on inhibitory approaches such as vaccines.

An ApiAP2 transcription factor influencing virulence gene transcription and sexual development in Plasmodium falciparum

“…The var PF3D7_0400400, upregulated after knockdown and recovery of PfAP2-O, is the so-called varsevere 42 of the upsA var group of which expression is upregulated in severe malaria cases 43 and in the onset of infection in non-immune individuals 44 . In endemic areas, the disruption of cytoadherence remains a challenge in the treatment of patients with severe malaria 45 We also investigated the role of PfAP2-O in parasite transmission through mosquito infection.…”

Association of EPCR Polymorphism rs867186-GG With Severity of Human Malaria

“…The binding of PfEMP1 to different host receptors determines the amount of sequestration and is associated with disease severity (Newbold et al, 1997;Wassmer et al, 2004;Ochola et al, 2011). PfEMP1 has been found to bind to CD36 on platelets via CIDRa2-6 domains in uncomplicated/mild malaria (UM/MM) (Mkumbaye et al, 2017;Mustaffa et al, 2017), and to ICAM-1 on endothelial cells in severe malaria (SM) via DBLb5 domains (Mustaffa et al, 2017;Tuikue Ndam et al, 2017). Recently, PfEMP1was found to interact with EPCR through CIDRa1 of domain cassette 8 (DC8) and DC13 in SM (Turner et al, 2013).…”

A meta-analysis of the endothelial protein C receptor rs867186 genotype in malaria

“…DBL-CIDR in tandem within N-terminus is referred to as the semi-conserved protein head structure and is the most conserved extracellular region [14]. CIDRα1 domains of PfEMP1 bind endothelial protein C receptor (EPCR) [11,15], while CIDRα2-6 domains of PfEMP1 bind to CD36 [11,15], and DBLβ5 domains bind to intercellular adhesion molecule 1 (ICAM-1) [13,15]. The parasite sequestration, which is associated with disease severity, is determined by the binding of PfEMP1 to host endothelial cell receptors mentioned above [16][17][18].…”