Malaria's deadly grip: cytoadhesion ofPlasmodium falciparum-infected erythrocytes

Abstract

Summary Cytoadhesion of Plasmodium falciparum infected erythrocytes to host microvasculature is a key virulence determinant. Parasite binding is mediated by a large family of clonally variant adhesion proteins, termed P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by var genes and expressed at the infected-erythrocyte surface. Although PfEMP1 proteins have extensively diverged under opposing selection pressure to maintain ligand binding while avoiding antibody-mediated detection, recent work has revealed they can be classified into different groups based on chromosome location and domain composition. This grouping reflects functional specialization of PfEMP1 proteins for different human host and microvascular binding niches and appears to be maintained by gene recombination hierarchies. In one extreme, a specific PfEMP1 variant is associated with placental binding and malaria during pregnancy, while other PfEMP1 subtypes appear to be specialized for infection of malaria naïve hosts. Here, we discuss recent findings on the origins and evolution of the var gene family, the structure-function of PfEMP1 proteins, and a distinct subset of PfEMP1 variants that have been associated with severe childhood malaria.

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…25 Sequestration results from the adhesion, or cytoadherence, of IRBC to vascular endothelial cells, and the process is mediated by the variant parasite ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of IRBC, and endothelial receptors, of which a number have been implicated. 54,55 Cytoadherence occurs to any significant extent only with P. falciparum that infects human Figure 2. Sequestration of P. falciparum-infected erythrocytes in human brain microvessels.…”

“…The majority of PfEMP1 variants bind to CD36, an 88-k D class B scavenger protein expressed on a number of cell types, including macrophages and endothelial cells. 54 Adhesion of IRBC to CD36 has been shown to recruit CD36 and actin to the site of attachment in human dermal microvascular endothelial cells through the activation of p130 CAS and Src family kinases. 56 Although there is no clear evidence of stress fiber formation, the actin cytoskeletal rearrangement may lead to a change in cell shape and hence affect the integrity of adherens junctions.…”

Sequence variation and structural conservation allows development of novel function and immune evasion in parasite surface protein families

“…In the most deadly forms of malaria, caused by Plasmodium falciparum , adhesive PfEMP1 proteins are present on the surface of infected erythrocytes 5. These DBL domain containing proteins mediate attachment to tissues and endothelial surfaces, holding the parasites away from splenic clearance and allowing them to divide and develop.…”

Towards an anti-disease malaria vaccine

“…This prevents infected erythrocytes, which have been swollen by parasites within, from being filtered from the blood by the human spleen. It also leads to inflammation, occlusion of blood vessels and to the symptoms of severe malaria, including cerebral malaria and pregnancy-associated malaria, which are characterized by marked sequestration of parasites in the brain and placenta [12]. Endothelial tethering is mediated by the P. falciparum erythrocyte membrane protein 1, PfEMP1, a large protein family with ∼60 members encoded in each genome [13,14].…”

“…Later, CIDRα1 domains were found to bind to human EPCR [16], thereby preventing EPCR from interacting with its natural ligand, activated protein C [16,36] (Figure 1). The blockage of EPCR-mediated signalling, through PfEMP1 binding, is proposed to lead to localized inflammation and to symptoms of severe disease [12,16,36,37].…”