Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: A parasite adhesion trait implicated in cerebral malaria

Abstract

Binding of infected erythrocytes to brain venules is a central pathogenic event in the lethal malaria disease complication, cerebral malaria. The only parasite adhesion trait linked to cerebral sequestration is binding to intercellular adhesion molecule-1 (ICAM-1). In this report, we show that Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binds ICAM-1. We have cloned and expressed PfEMP1 recombinant proteins from the A4tres parasite. Using heterologous expression in mammalian cells, the minimal ICAM-1 binding domain was a complex domain consisting of the second Duffy binding-like (DBL) domain and the C2 domain. Constructs that contained either domain alone did not bind ICAM-1. Based on phylogenetic criteria, there are five distinct PfEMP1 DBL types designated α, β, γ, δ, and ɛ. The DBL domain from the A4tres that binds ICAM-1 is DBLβ type. A PfEMP1 cloned from a distinct ICAM-1 binding variant, the A4 parasite, contains a DBLβ domain and a C2 domain in tandem arrangement similar to the A4tres PfEMP1. Anti-PfEMP1 antisera implicate the DBLβ domain from A4var PfEMP1 in ICAM-1 adhesion. The identification of a P. falciparum ICAM-1 binding domain may clarify mechanisms responsible for the pathogenesis of cerebral malaria and lead to interventions or vaccines that reduce malarial disease.

Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36

“…Cells were analyzed for surface expression by immunofluorescence 48 hours later with mAb 179 (Affymax Research Institute), which recognizes an epitope tag at the carboxy terminal of the insert. 31,36 Cell lines stably expressing CIDR-1 domains were transfected and selected as described elsewhere. 29,31,36 …”

“…31,36 Cell lines stably expressing CIDR-1 domains were transfected and selected as described elsewhere. 29,31,36 …”

“…35 The CIDR-1 domain, located after the first DBL domain, was described as the binding domain for CD36, 33 whereas the DBL␤-C2 and DBL␥ bind, respectively, to ICAM-1 and CSA. 29,31 Interestingly, the CIDR-1 domain from CSA-adherent parasites is not significantly different from the CIDR-1 domains that bind CD36. No gross changes are found in the minimal CD36-binding region of CIDR-1, and all cysteine residues critical for CD36 binding are conserved.…”

“…[26][27][28] PfEMP-1 is expressed on the erythrocyte surface and mediates binding to several adhesion receptors, including CD36, TSP, ICAM-1, PECAM, and CSA. [29][30][31][32][33][34] PfEMP-1 possesses 2 adhesive modules: the cysteine-rich interdomain regions (CIDRs) and the Duffy binding-like (DBL) domains. 35 The CIDR-1 domain, located after the first DBL domain, was described as the binding domain for CD36, 33 whereas the DBL␤-C2 and DBL␥ bind, respectively, to ICAM-1 and CSA.…”

Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease

“…DBL-1a, with its clusters of glycosaminoglycan (GAG)-binding motifs, is believed to mediate the formation of rosettes (i.e. binding of infected erythrocytes to uninfected erythrocytes) (Chen et al 1998), which have been linked to the pathogenesis of CM (Newbold et al 1999), whereas DBL-1b binds to ICAM-1 (Smith et al 2000 ;Oleinikov et al 2009) and DBLc binds to chondroitin suphate A (CSA) (Reeder et al 1999 ;Buffet et al 1999 ;Gamain et al 2004), the latter interaction mediating tissue-specific sequestration of pRBC in the placenta. Disease association studies have suggested that differences in CIDRs and DBLs between commonly expressed var genes may contribute to variations in parasite virulence Normark et al 2007), such that some parasite isolates are more likely than others to sequester in particular tissues and therefore cause differing clinical presentations, but -with the exception of particular PfEMP-1 molecules that favour placental sequestration (Fried and Duffy, 2002 ;Salanti et al 2004) -direct evidence to support this hypothesis is lacking.…”