Malaria's deadly grip: cytoadhesion of Plasmodium falciparum-infected erythrocytes

Abstract

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. Inone 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.

Fig. 1

Var gene organization and protein domain architectures. A. Chromosomal organization of var genes. Group B and A var genes are located in the subtelomeric regions and transcribed in opposite orientations. Group C are typically found on central chromosome clusters. B. There is a recombination hot spot between subdomains 2 and 3 in the DBL domain of the PfEMP1 head structure. DC8 is an unusual chimeric gene between a group B and group A var gene. C. Different types of DBL and CIDR domains are located at the N- and C-terminus of proteins. Small PfEMP1 have four extracellular domains, large PfEMP1 have additional DBL domains after the head structure or the second DBL-CIDR structure.

Fig. 2

Model of PfEMP1 head structure divergence. The PfEMP1 head structure has diverged into three major binding groups under selection for EPCR-binding, CD36-binding, or to form rosettes with uninfected erythrocytes. The proportion of different head structure types in the 3D7 reference genome isolate and their predicted binding properties is shown. Note there may be some binding exceptions (e.g. only a subset of CIDRα1 domains bind EPCR, see Fig. 1). CD36 binding is the most common PfEMP1 adhesion trait and is associated with mild malaria. EPCR-binding and rosetting is linked to group A head structures. Group A PfEMP1 tend to be expressed in early childhood infections or malaria naïve, and are also associated with severe malaria. Under normal circumstances, protein C (PC) binds to EPCR and is activated by the thrombin (T)/thrombomodulin (TM) complex. Activated protein C (APC) that is released into the plasma has anti-coagulant activity and the APC/EPCR complex activates the protease activated receptor 1 (PAR1) to mediate intracellular signaling. The protein C-EPCR signalling pathway has anti-inflammatory, anti-thrombotic and endothelial cytoprotective activities that help maintain vascular integrity (Mosnier et al., 2007). The loss of EPCR at sites of P. falciparum IE sequestration (Moxon et al., 2013) and EPCR-binding parasites (Turner et al., 2013) may combine to interfere or subvert these pathways and contribute to disease pathogenesis.