PARASITE VIRULENCE FACTORS DURING FALCIPARUM-MALARIA - ROSETTING, CYTOADHERENCE, AND MODULATION OF CYTOADHERENCE BY CYTOKINES

To determine virulence factors of isolates of Plasmodium falciparum an d the potential role of cytokines in cerebral malaria, 46 Malagasy pat ients presenting with cerebral (n = 10), severe (n = 10), and uncompli cated (n = 26) malaria were enrolled in a study. The capacity of 21 of 46 P. falciparum isolates to form rosettes in vitro and to adhere to human umbilical vein endothelial cells (HUVECs) that express intercell ular adhesion molecule-1 receptors and to C32 amelanotic melanoma cell s that express mainly CD36 receptors was investigated together with th e effects of tumor necrosis factor alpha (TNF-alpha), granulocyte macr ophage-colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and I L-6 alone and in two-by-two combinations on the cytoadherence of infec ted erythrocytes to HUVECs. Plasma levels of these cytokines were also measured in the patients at admission. The percentage of rosette form ation was higher for the isolates from patients with cerebral (n = 6; 19.5%) and severe (n = 6; 30.5%) malaria than for those from patients with uncomplicated malaria (n = 9; 5%) (P < 0.002). The cytoadherence properties of the isolates did not differ among the three groups whate ver the target cell used, but adherence to melanoma cells was systemat ically higher than that to HUVECs. Adhesion to HUVECs was increased mo re after TNF-alpha stimulation than after GM-CSF, IL-3, or IL-6 stimul ation (P < 0.01). Only the combination of TNF-alpha and IL-3 enhanced cytoadherence more than TNF-alpha used alone (P < 0.02). No difference in the modulation of cytoadherence by cytokines was found in relation to the severity of the disease. TNF-alpha and IL-6 levels in peripher al blood were higher in the patients with cerebral and severe malaria than in the patients with uncomplicated malaria (P < 0.005). Most of t he patients' sera contained little or no IL-3 or GM-CSF. Our results c hallenge the role of intercellular adhesion molecule-1 as the principa l receptor mediating the cytoadherence of P. falciparium-infected eryt hrocytes and contrast with data obtained in the murine model.