Falciparum malaria is characterized by cytoadherence of host erythrocytes containing mature asexual-stage parasites and the consequent sequestration of these forms in tissue microvasculature. A postmortem study of pediatric malaria provided us with the opportunity to compare the genetic complexity of circulating and sequestered Plasmodium falciparum populations, in patients with fatal cerebral malaria (CM) versus control subjects with incidental P. falciparum parasitemia who died of causes other than malaria. Parasite genotypes identified in peripheral blood collected at the time of admission to the hospital constituted a subset of those detected in the tissues at death. Despite a higher tissue burden of parasitized erythrocytes in patients with CM than in parasitemic control subjects, parasite populations in tissues from patients with CM were less genetically complex, and the genotypes were more homogeneously distributed throughout the body, than in patients with incidental infection. Our findings support the notion that CM is associated with the emergence of a small number of dominant genotypes in an infected individual.

SummaryAdhesion of human erythrocytes infected with the malaria parasite Plasmodium falciparum to host endothelium has been associated with severe forms of this disease. A number of endothelial receptors have been identified, and there is evidence that one of these, intercellular adhesion molecule-1 (ICAM-1), may play an important role in the pathology of cerebral malaria. Mutagenesis of domain 1 of ICAM-1, which is involved in parasite adhesion, shows that the binding sites for different parasite variants overlap to a large extent, but that there are subtle differences between them that correlate with their adhesive phenotypes. This suggests that the ability to bind to ICAM-1 has arisen from a common variant, but that subsequent changes have led to differences in binding avidity, which may affect pathogenesis. The definition of common binding determinants and the elucidation of links between ICAM-1 binding phenotype and disease will provide new leads in the design of therapeutic interventions.

Adhesion of Plasmodium falciparum-infected erythrocytes (IE) to host endothelium has been associated with pathology in malaria. Although the interaction with endothelial cells can be complex due to the relatively large number of host receptors available for binding, specific proteins have been identified that are more commonly used than others. For example, binding to intercellular adhesion molecule 1 (ICAM 1) is found frequently in parasites from pediatric cases of malaria. The binding site for P. falciparum-infected erythrocytes on ICAM 1 has been mapped in some detail and is distinct from the site for lymphocyte function-associated antigen 1 (LFA-1). Part of the ICAM 1 binding site for P. falciparum-infected erythrocytes (the DE loop) was used to screen a library of compounds based on its structure (derived from the crystal structure of human ICAM 1). This resulted in the identification of 36 structural mimeotopes as potential competitive inhibitors of binding. One of these compounds, (؉)-epigalloyl-catechin-gallate [(؉)-EGCG], was found to inhibit IE adhesion to ICAM 1 in a dose-dependent manner with two variant ICAM 1-binding parasite lines, providing the first example of a potential mimeotope-based anticytoadherence inhibitor for Plasmodium falciparum.Malaria imposes a huge burden of mortality and morbidity in developing countries (25), particularly in sub-Saharan Africa, where it is responsible for over 1 million deaths per year. Most of these are caused by infection with Plasmodium falciparum, one of four human malaria parasites and the only one to undergo significant adhesion to host endothelium, resulting in the sequestration of mature erythrocytic-stage infected erythrocytes (IE) from the peripheral circulation. The pathology of P. falciparum malaria is complex and comprises a number of syndromes, at least some of which are thought to be related to the ability of IE to adhere to host small-vessel endothelium. Several endothelial receptors have been implicated in this interaction (for a review, see reference 9), including intercellular adhesion molecule 1 (ICAM 1) (5). For IE that use ICAM 1, the receptor appears to be an important component of binding, as inhibition using specific monoclonal antibodies reduces cytoadherence to almost background levels despite the presence of other receptors, such as CD36 (12). Although there is some evidence associating sequestration with severe disease, the identification of specific receptor usage linked with pathology has been difficult, with different studies producing conflicting conclusions. In one large study in Kenya, the ability of patient isolates to bind to ICAM 1 was linked to disease (with a trend toward cerebral malaria, a serious, life-threatening manifestation of disease) (14). However, other studies have shown no effect (18). Despite these difficulties, it seems likely that being able to prevent or reverse adhesion to endothelium will be beneficial in acute disease by providing direct access by host clearance systems to the sequestered mass of parasit...

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