Structure-Guided Identification of a Family of Dual Receptor-Binding PfEMP1 that Is Associated with Cerebral Malaria

Abstract

SummaryCerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified. Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone. Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors. Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria. This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.

Towards an anti-disease malaria vaccine

“…While expression of EPCR-binding PfEMP1s has been associated with all forms of severe malaria [16,[38][39][40][41], probably due to broad tissue tropism, efficient sequestration and the proposed pathogenic consequences of receptor binding, it is not specially linked to the development of cerebral disease. A particular association with cerebral symptoms was found for parasites expressing PfEMP1s that combine both an EPCR-binding CIDRα1 domain and a DBLβ domain that can bind to ICAM-1, allowing simultaneous binding of infected erythrocytes to both ligands [38,42,43] (Figure 1).…”

“…A particular association with cerebral symptoms was found for parasites expressing PfEMP1s that combine both an EPCR-binding CIDRα1 domain and a DBLβ domain that can bind to ICAM-1, allowing simultaneous binding of infected erythrocytes to both ligands [38,42,43] (Figure 1). (A) The architecture of PfEMP1 ectodomains displayed on the surface of erythrocytes infected with P. falciparum.…”

“…(C) Crystal structure of a DBL domain (green) bound to the first two domains of its human receptor, ICAM-1 (blue). The inset shows the DBL residues (red) that directly contact ICAM-1 and a sequence logo showing their conservation across 145 ICAM-1-binding DBL domains [38].…”

“…The links between these PfEMP1 types and severe or cerebral malaria are not absolute [16,38,44]. Nevertheless, expression of these PfEMP1s is a significant risk factor for the development of severe malaria symptoms and inhibitory antibodies targeting their respective receptor-binding domains are found in surviving patients [36,38].…”

“…Nevertheless, expression of these PfEMP1s is a significant risk factor for the development of severe malaria symptoms and inhibitory antibodies targeting their respective receptor-binding domains are found in surviving patients [36,38]. While there is still much to discover about the PfEMP1s, these groups of domains are therefore highly promising candidates to target in attempts to reduce the devastating symptoms of severe malaria.…”