Adherence of trophozoite and schizont-infected erythrocytes in target organs appears to be a major feature of the pathophysiology of P. falciparum malaria. As parasites mature, the infected erythrocytes become more rigid, less deformable, and changes occur in parasite and host surface proteins. One of the main changes in the host is the aggregation of Band 3, which leads to expression of 'senescence' antigen.

Infected cells usually adhere at the site of parasite-dependent electron-dense protrusions of the red cell membrane (referred to as 'knobs'). In addition, clonally derived populations of P. falciparum are able to alter parasite antigens expressed on the red cell surface, a process known as antigenic variation (Biggs et al., 1991). Selection of isolates for a particular cytoadherence phenotype is associated with antigenic variation, suggesting that the variant antigen is involved in cytoadherence (Biggs et al., 1992). One variant antigen expressed at the surface of malaria-infected cells is known as P. falciparum erythro-cyte membrane protein 1 (PfEMP1). PfEMP1 can bind to many receptors, including CD36 (Baruch et al., 1995), and is usually expressed in conjunction with knobs. The var genes encoding this family of proteins have been identified and sequenced (Baruch et al., 1995; Su et al., 1995) but there may be other families of variant antigens that are also expressed at the surface of infected cells.

Many putative endothelial cytoadherence receptors have been described in vitro, and thrombospondin, CD36, ICAM-1, PECAM, VCAM and chondroitin sulphate A all support binding of some, but not all, P. falciparum infected erythrocytes in vitro (Figure 3.4). Field isolates may bind to any of these receptors, but CD36 binds the highest proportion of isolates. Binding of parasitised cells cultured from peripheral blood does not correlate with particular pathology, but a remarkably high proportion of infected cells harvested from placenta are able to bind to chondroitin sulphate A, suggesting that these may be markers for placental sequestration (Fried and Duffy, 1998; Beeson et al., 1999) or hyaluronic acid (Beeson et al., 2000). Parasite toxins and cytokines increase expression of surface endothelial ligands, thus contributing to a vicious cycle when sequestered cells mature and rupture, causing local cytokine release and upregulation of receptors, thus favouring sequestration of the next brood of parasites.

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