A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies

Abstract

Cerebral Plasmodium falciparum malaria is characterized by adhesion of infected erythrocytes (IEs) to the cerebral microvasculature. This has been linked to parasites expressing the structurally related group A subset of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of IE adhesion ligands and to IEs with affinity for ICAM-1. However, recent evidence has cast doubt on both these associations, tempering hopes of the feasibility of developing a vaccine based on ICAM-1–binding PfEMP1. In this study, we report the identification of a domain cassette (DC) present in group A var genes from six genetically distinct P. falciparum parasites. The three domains in the cassette, which we call DC4, had a high level of sequence identity and cluster together phylogenetically. Erythrocytes infected by these parasites and selected in vitro for expression of DC4 adhered specifically to ICAM-1. The ICAM-1–binding capacity of DC4 was mapped to the C-terminal third of its Duffy-binding–like β3 domain. DC4 was the target of broadly cross-reactive and adhesion-inhibitory IgG Abs, and levels of DC4-specific and adhesion-inhibitory IgG increased with age among P. falciparum–exposed children. Our study challenges earlier conclusions that group A PfEMP1 proteins are not central to ICAM-1–specific IE adhesion and support the feasibility of developing a vaccine preventing cerebral malaria by inhibiting cerebral IE sequestration.

IgG Antibodies to Endothelial Protein C Receptor-Binding Cysteine-Rich Interdomain Region Domains of Plasmodium falciparum Erythrocyte Membrane Protein 1 Are Acquired Early in Life in Individuals Exposed to Malaria

“…The attachment is mediated by different members of the large family of PfEMP1 proteins (16)(17)(18)(19), which can bind to receptors with nanomolar affinity and thereby anchor infected erythrocytes to endothelial cells and syncytiotrophoblasts (28,36). Individuals exposed to malaria infections acquire IgG recognizing PfEMP1 expressed on the surface of infected erythrocytes, and some of these antibodies can inhibit the interaction between specific PfEMP1s and their binding partners (29,(37)(38)(39)(40)(41)(42) (Fig. 4).…”

The Severity of Plasmodium falciparum Infection Is Associated with Transcript Levels of var Genes Encoding Endothelial Protein C Receptor-Binding P. falciparum Erythrocyte Membrane Protein 1

“…The DBL␤, -␥, and -␦ domain classes each cover broad sequence variation and include few well-defined subclasses, which makes it difficult to design subclass-specific primers that retain target coverage. However, a few distinct loci were identified in a subset of sequences encoding the DBL␤1/3 and DBL␤5 domains, including some sequence variants previously associated with ICAM-1 binding (30,32,33). Primers targeting these loci did not report significantly different levels between patients with severe and those with uncomplicated malaria.…”

Plasmodium falciparum picks (on) EPCR

“…Identifying specific interactions between particular PfEMP1 domains and EPCR sets a precedent for the discovery of others, such as the recent identification of PfEMP1 DC4 as the ligand for ICAM-1 and DC5 as the ligand for CD31 (PECAM-1). 28,29 Are additional PfEMP1 host-receptor interactions involved in the pathogenesis of other organ-specific malaria syndromes (all of which can occur in isolation) such as respiratory distress, renal failure, and severe anemia? The sickle-cell trait, which provides remarkable protection against CM, has been shown to affect the amount and distribution of PfEMP1 on the surface of IEs, resulting in weakened cytoadherence interactions.…”