Review
Falciparum Malaria: Sticking up, Standing out and Out-standing

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Abstract

Cytoadherence is believed to be fundamental for the survival of Plasmodium falciparum in vivo and, uniquely, is a major determinant of the virulence of this parasite. Despite the widely professed importance of cytoadhesion in the development of severe disease, there are a number of aspects of this highly complex process that remain poorly understood. Recent progress in the understanding of cytoadhesive phenomena was discussed extensively at the Molecular Approaches to Malaria conference, Lorne, Australia, 2–5 February 2000. Here, Brian Cooke, Mats Wahlgren and Ross Coppel consider just how far we have progressed during the past 30 years and highlight what is still missing in our understanding of the mechanisms and clinical relevance of this apparently vital process.

Section snippets

Why focus on cytoadherence?

We believe that cytoadherence is a key determinant of parasite virulence and is responsible for the development of severe disease in malaria, or at least, that part of severe disease associated with frequently fatal syndromes such as cerebral malaria (CM). By the late 19th century, clinicians had already recognized that P. falciparum, a species that sequestered in the microvasculature, was more virulent in humans than was P. vivax, a species that did not sequester. In 1985, Langreth and

From cytoadherence to clinical disease

The overwhelming conclusion from studies over the past five years is that cytoadherence is undoubtedly incredibly complex. We seem to have described more receptors to which PRBC can bind than we really need to explain the pathophysiology (Fig. 1). Other pathogens, including viruses and bacteria, seem to make do with just one or two receptors for invasion, survival and propagation in vivo, so why should P. falciparum require such a complex ensemble? How do we make sense of which are the more

New receptors and ligands

Although new studies addressing some unanswered questions were presented at the conference, generally, more questions were generated than definitive answers were gained. At least two further receptors, one new RBC-expressed ligand and one additional cellular interaction were described to add to the complexity of the situation. Beeson and co-workers (The Walter & Eliza Hall Institute, Melbourne, Australia) described the identification of hyaluronic acid (HA) as a new receptor for PRBC in the

PfEMP1, RIFINs and Pf60 proteins

Much recent effort has also focused on the precise mapping of multiple functional domains of PfEMP1. The complex and highly variable extracellular head structure of the molecule is composed of between two and seven DBL domains and one or two CIDRs (Cys-rich-inter-domain regions). Specific and distinct domains of PfEMP1 have now been identified that mediate binding to a number of endothelial-cell-expressed receptors (see Fig. 1) as well as to normal, non-immune human serum immunoglobulins (IgM

Future focus

In our view, this area of research is going to become increasingly more complicated, with further interactions, receptors, ligands and functional domains described. The polymorphism of the PfEMP1 family is such that individual members will have measurable affinity with even more molecules than we are currently aware. We should also have a much clearer understanding of how this and other multigene families are controlled. The challenge will be not to lose ourselves in the molecular detail, but

Website of Interest

Malaria Transmission Blocking Vaccines: An Ideal Public Good A document published by WHO under this title can be downloaded from http://www.who.int/tdr/publications/publications/pdf/tbv.pdf

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