PfEMP1: An antigen that plays a key role in the pathogenicity and immune evasion of the malaria parasite Plasmodium falciparum

Abstract

The deadliest form of human malaria is caused by the protozoan parasite Plasmodium falciparum affecting millions worldwide every year. P. falciparum virulence is attributed to its ability to evade the human immune system by modifying infected host red blood cells to adhere to the vascular endothelium and to undergo antigenic variation. The main antigenic ligands responsible for both cytoadherence and antigenic variation are members of the P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1) family. These polymorphic proteins are encoded by a multi-copy gene family called var. Each individual parasite expresses a single var gene at a time, maintaining the remaining ∼60 var genes found in its genome in a transcriptionally silent state. As the antibody response against the single expressed PfEMP1 develops, small sub-populations of parasites switch expression to alternative forms of PfEMP1 and re-establish the infection. Therefore, PfEMP1 is considered a key player in the pathogenicity of P. falciparum.

Introduction

Malaria is one of the major infectious diseases influencing human kind today. Each year 300–600 million people worldwide are infected with malaria parasites. Plasmodium falciparum is the Apicomplexan parasite responsible for the deadliest form of human malaria causing 1–3 million deaths a year, primarily of young African children (Snow et al., 2005). P. falciparum is transmitted by Anopheline mosquitoes and replicates within the circulating red blood cells of an infected individual. The virulence of P. falciparum is attributed to the parasites’ ability to modify the erythrocyte surface to adhere and to evade the host immune attack. The major antigenic ligand found to be responsible for the cytoadhesive properties of the infected red blood cells (iRBC) are members of the P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1) family. These antigenically variable proteins are placed on knob like structures on the surface of the iRBC and bind to different host vascular adhesins, including CD36, ICAM1, VCAM1, and CSA (Kraemer and Smith, 2006). Different binding phenotypes cause sequestration in different organs and contribute to life threatening manifestations of the disease. PfEMP1 is also a major surface antigen that mediates antibody-dependent immune response. This response often clears the majority of infected cells from the circulation. However, small sub-populations of parasites switch expression to a different PfEMP1 avoid the antibody response and re-establish infection (Smith et al., 1995). This process is referred to as antigenic variation and is responsible for the persistent nature of the disease, as well as the waves of parasitemia, typical for P. falciparum infections (Miller et al., 1994). The extreme antigenic variability and the great breadth in adhesive phenotypes within the PfEMP1 repertoire make it the principal virulence factor of malaria.