Cell-cell interaction in the pathogenesis of severe falciparum malaria

One of the major unresolved questions in malaria is why some patients with Plasmodium falciparum infection become so sick and die. Cell-cell interactions between the parasite and the host involving adherence/invasion appear generally, but not exclusively, to correlate with severity. The most important of these interactions in the asexual blood cycle are: (i) the invasion of red cells by merozoites, (ii) the binding of parasitised red blood cells (PRBC) to uninfected red cells (rosetting), (iii) the binding of PRBC to endothelial cells in critical organs (cytoadherence) and (iv) the induction of pro-inflammatory cytokines by PRBC, notably tumour necrosis factor (TNFalpha). The resulting clinical manifestations are protean. Analysis of these cellular interactions has revealed marked heterogeneity in molecular specificity which highlights the complexity of pathogenesis, but also opens the way to new modalities for treating this deadly infection.