Molecular Pathogenesis of Cerebral Malaria

Abstract

Plasmodium falciparum, the most malignant human malaria, is responsible for 2-3 million deaths annually. These infections often involve blockage of the cerebral microvasculature by P. falciparum-infected erythrocytes (Fig. 1). This aspect is considered the major factor in the pathogenesis of cerebral malaria.Upon invasion of the erythrocyte, P. falciparum immediately begins to remodel the infected erythrocyte. The adherence points of infected erythrocytes, termed knobs (Fig. 2 and 3), contain antigenically diverse 200-350kDa surface proteins (PfEMPl; Fig. 4). The PfEMPl variant surface proteins are encoded by a large and extremely diverse family of genes (var), and switches in the expression of var genes account for rapid changes in the antigenic and adhesive properties of P. falciparum-inkcted erythrocytes (2.4% per generation). Switches in the PfEMPl expression may not only affect the phenotype of the parasite strain but may also change its sequestration to endothelial cells. Genetic reorganization in this protein can lead to binding any of the following endothelial cell receptors; ICAM-1, CD36, thrombospondin, chondroitin sulfate (Fig. 5),2 ELAM-1, or VCAM-1.