GLYCOSYLPHOSPHATIDYLINOSITOL TOXIN OF PLASMODIUM UP-REGULATES INTERCELLULAR-ADHESION MOLECULE-1, VASCULAR CELL-ADHESION MOLECULE-1, AND E-SELECTIN EXPRESSION IN VASCULAR ENDOTHELIAL-CELLS AND INCREASES LEUKOCYTE AND PARASITE CYTOADHERENCE VIA TYROSINE KINASE-DEPENDENT SIGNAL-TRANSDUCTION

In this study we demonstrate that glycosylphosphatidylinositol (GPI) o f malaria parasite origin directly increases cell adhesion molecule ex pression in purified HUVECs in a dose- and time-dependent manner, resu lting in a marked increase in parasite and leukocyte cytoadherence to these target cells. The structurally related glycolipids dipalmitoyl-p hosphatidylinositol and iM4 glycoinositolphospholipid of Leishmania me xicana had no such activity. Malarial GPI exerts this effect by activa tion of an endogenous GPI-based signal transduction pathway in endothe lial cells, GPI induces rapid onset tyrosine phosphorylation of multip le intracellular substrates within 1 min of addition to cells in a dos e-dependent manner, This activity can be blocked by the protein tyrosi ne kinase-specific antagonist herbimycin A, genistein, and tyrphostin. These tyrosine kinase antagonists also inhibit GPI-mediated up-regula tion of adhesin expression and parasite cytoadherence. GPI-induced up- regulation of adhesin expression and parasite cytoadherence can also b e blocked by the NF kappa B/c-rel antagonist pyrrolidine-dithiocarbama te, suggesting the involvement of this family of transcription factors in GPI-induced adhesin expression. The direct activation of endotheli al cells by GPI does not require the participation of TNF or IL-1. How ever, GPI is also responsible for the indirect pathway of increased ad hesin expression mediated by TNF and IL-1 output from monocytes/macrop hages. Total parasite extracts also up-regulate adhesin expression and parasite cytoadherence in HUVECs, and this activity is blocked by a n eutralizing mAb to malarial GPI, suggesting that GPI is the dominant a gent of parasite origin responsible for this activity. Thus, a parasit e-derived GPI toxin activates vascular endothelial cells by tyrosine k inase-mediated signal transduction, leading to NF kappa B/c-rel activa tion and downstream expression of adhesins, events that may play a cen tral role in the etiology of cerebral malaria.