Review: Multigene families. 3.
Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in malaria pathogenesis and immune evasion

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Abstract

The surface of the erythrocyte undergoes a number of modifications during infection by Plasmodium falciparum. These modifications are critical for pathogenesis of severe disease and the acquisition of host immunity through their role in interactions between the host and the parasite and in antigenic variation. Our knowledge of the molecular basis for these processes has increased dramatically over the last few years, through a combination of genomic and biochemical studies. This review provides a summary of the molecules involved in cytoadherence and antigenic variation in P. falciparum.

Introduction

Malaria remains one of the major infectious diseases in tropical and subtropical areas, causing a huge burden of mortality and morbidity in developing countries. The death toll for malaria is high with approximately 1 million fatalities every year, but this represents a relatively small percentage of the total number of cases of malaria. In malaria-holoendemic areas, clinically protective immunity is acquired during the first 5–10 years of life so that most of the severe disease in these areas is found in young children. As the parasite develops in the host's erythrocyte, a number of changes takes place including modifications to the cell membrane to form knob-like structures and increasing the rigidity of the cell, alterations in metabolite transport and the insertion of a number of parasite-derived proteins into the surface of the infected-erythrocyte membrane. The importance of these changes is not fully understood but the development of immunity to malaria is thought to involve responses to the malarial antigens expressed at the surface of infected erythrocytes [1], [2], [3]. Until recently, these antigens were poorly defined in molecular terms but a combination of genomic and biological research has begun to address this important area of research.

Section snippets

PfEMP1 (var genes)

Perhaps, the most well known protein on the surface of the infected erythrocyte (IE) is Plasmodium falciparum erythrocyte membrane protein-1, or PfEMP1. This was originally defined biochemically as a high molecular weight, surface-labellable, triton insoluble protein of variable molecular weight [4]. The genes encoding these proteins have been identified as the var family [5], [6], [7]. There are 40–50 var genes per haploid genome, which are predominantly situated in the subtelomeric regions of

Modified band 3

Band 3 is a highly abundant erythrocyte host protein that acts as an anion transporter for the erythrocyte. Cryptic epitopes of this protein are exposed in ageing erythrocytes as part of a mechanism for the removal of senescent cells. Infection by P. falciparum also causes structural modifications to band 3 that can be recognised using specific monoclonal antibodies (mAbs) that also inhibit cytoadherence to C32 melanomas [38], [39]. The regions of modified band 3 that are involved in this

Adhesion phenotypes

Many of the surface molecules described above are thought to play some role in adhesion. For P. falciparum, more than ten host receptors have been identified (Table 2), although not all of these appear to play a major role in patient isolates. IEs are able to bind to a range of receptors with each parasite having the ability to bind to a subset of them. With the identification of the var genes it has been proposed that the DBL regions may represent binding sites [9] and that the combination of

Antigenic variation in other malaria species

Besides P. falciparum, a number of other malaria species exhibit the sequential appearance of successive variant antigenic molecules at the surface of infected erythrocytes such as Plasmodium knowlesi [108], Plasmodium chabaudi [109] and Plasmodium fragile [110]. Variable surface antigens have also been described for P. vivax [111] and it is assumed that antigenic variation is a general phenomenon in malaria parasites. Since sequestration does not occur in all species, it has been recently

Conclusions and perspectives

Since the description of the var gene family in 1995, several studies have established a molecular framework with regard to the regulation of var genes. All available data point to epigenetic gene regulation with the potential role of reversible chromatin modifications and/or nuclear architecture. A number of interesting questions concerning var gene biology remain to be answered: is there an ordered switching of var genes as has been reported for P. fragile [110], do in vitro switch rates

Summary

Our knowledge of the IE has progressed rapidly over the last five years. What was once thought to be a rather sparse ‘landscape’ has become a complex interface between the parasite and the host. Given the importance of this interaction in pathogenesis and immunity, research into these molecules has the potential to provide new avenues for interventions in malaria.

Uncited references

[119], [120]

Acknowledgements

We would like to thank D. Mattei, P. David, L.H. Freitas-Junior, M. Chance and M. Hommel for critically reading the manuscript. We also thank R. Hernandez-Rivas, L. da Silva, P. Preiser and M. Wahlgren for communicating unpublished data. This work has been supported by a grants from the Commission of the European Communities for research and technical development (Contract No. CT98-0362 and QLK2-CT-2000-00109) and the Wellcome Trust.

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