Abstract
Background Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) is a highly polymorphic adherence receptor expressed on the surface of infected erythrocytes. Based on sequence homology PfEMP-1 variants have been grouped into three major groups A-C, the highly conserved VAR2CSA variants, and semi-conserved types defined by tandem runs of specific domains (“domain cassettes” (DC)). The PfEMP-1 type expressed determines the adherence phenotype, and is associated with clinical outcome of infection.MethodsParasite isolates from Beninese children or women presenting with, respectively, CM or PAM were collected along with samples from patients with uncomplicated malaria (UM). We assessed the transcript level of var genes by RT-qPCR and the expression of PfEMP-1 proteins by LC-MS/MS.Results Var genes encoding DC8 and Group A PfEMP-1 were transcribed more often and at higher levels in cerebral malaria vs. uncomplicated malaria patients. LC-MS/MS identified peptides from group A, DC8 PfEMP-1 more frequently in cerebral malaria than in uncomplicated malaria and pregnancy-associated malaria samples.ConclusionThis is the first study to show association between PfEMP-1 subtype and disease outcome by direct analysis of parasites proteome. The results corroborate that group A and specifically the PfEMP-1 types DC8 are universally associated with cerebral malaria. This is a crucial observation for promoting studies on malaria pathogenesis.
Highlights
Virulence of Plasmodium falciparum is linked to the sequestration of parasites in the host’s deep organ vasculature caused by cytoadherence of parasite infected erythrocytes to endothelial cell receptors [1,2]
This tissue tropism is mediated by members of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family expressed at the infected erythrocytes (iE) surface [3,4]
Binding specificity of Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) is thought to be associated with clinical syndromes. iE binding to Chondroitin-Sulfate A (CSA) is associated with pregnancy-associated malaria (PAM) [7], and adhesion to ICAM-1 appears to be associated with cerebral malaria (CM) [8,9]
Summary
Virulence of Plasmodium falciparum is linked to the sequestration of parasites in the host’s deep organ vasculature caused by cytoadherence of parasite infected erythrocytes (iE) to endothelial cell receptors [1,2]. This tissue tropism is mediated by members of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family expressed at the iE surface [3,4]. Based on sequence homology PfEMP-1 variants have been grouped into three major groups A-C, the highly conserved VAR2CSA variants, and semi-conserved types defined by tandem runs of specific domains (‘‘domain cassettes’’ (DC)). The PfEMP-1 type expressed determines the adherence phenotype, and is associated with clinical outcome of infection
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