AN IMMUNOHISTOCHEMICAL STUDY OF THE PATHOLOGY OF FATAL MALARIA - EVIDENCE FOR WIDESPREAD ENDOTHELIAL ACTIVATION AND A POTENTIAL ROLE FOR INTERCELLULAR-ADHESION MOLECULE-1 IN CEREBRAL SEQUESTRATION

The sequestration of parasitized erythrocytes in the microvasculature of vital organs is central to the pathogenesis of severe plasmodium fa lciparum malaria. This process is mediated by specific interactions be tween parasite adherence ligands and host receptors on vascular endoth elium such as intercellular adhesion molecule-1 (IGAM-1) and CD36. Usi ng immunohistochemistry we have examined the distribution of putative sequestration receptors in different organs from fatal cases of P. fal ciparum malaria and noninfected controls. Receptor expression and para site sequestration in the brain were quantified and correlated. Fatal malaria was associated with widespread induction of endothelial activa tion markers, with significantly higher levels of ICAM-1 and E-selecti n expression on vessels in the brain. In contrast cerebral endothelial CD36 and thrombospondin staining were sparse, with no evidence for in creased expression in malaria There was highly significant co-localiza tion of sequestration with the expression of ICAM-1, CD36, and E-selec tin in cerebral vessels but no cellular inflammatory response. These r esults suggest that these receptors have a role in sequestration in vi vo and indicate that systemic endothelial activation is a feature of f atal malaria.