Synergism of multiple adhesion molecules in mediating cytoadherence of Plasmodium falciparum–infected erythrocytes to microvascular endothelial cells under flow

Abstract

Plasmodium falciparum–infected erythrocytes (IRBCs) have been shown to interact with a number of endothelial adhesion molecules expressed on transfectants, on cell lines, and as immobilized purified receptor proteins under flow conditions. However, the experiments were designed in such a way that maximal numbers of adhesion molecules were provided as substratum. Whether the interactive events actually occur on microvascular endothelium, where the distribution and expression of adhesion molecules may be less, remains undetermined. In this study, the cytoadherance of IRBCs on human dermal microvascular endothelial cells (HDMECs) as a model of human microvasculature was examined. IRBCs were observed to tether, roll, and adhere on resting HDMECs, which constitutively expressed CD36 and intercellular adhesion molecule-1 (ICAM-1) at an optimal shear stress of 1 dyne/cm2. Stimulation of HDMECs with tumor necrosis factor–α for 5 and 24 hours, which resulted in up-regulation of ICAM-1 and induction of vascular cell adhesion molecule-1 expression, significantly increased the percentage of rolling cells that adhered without affecting the rolling flux. In contrast, P-selectin expression on HDMECs induced by oncostatin M led to an increase in both rolling flux and adhesion. Inhibition studies with receptor-specific monoclonal antibodies revealed that adhesion of IRBCs on HDMECs was largely CD36 dependent, whereas rolling could be mediated by any of the adhesion molecules studied. Collectively, these findings indicate that IRBCs interact synergistically with multiple adhesion molecules on vascular endothelium. The rolling of IRBCs may be the rate-limiting step in cytoadherance, since it can be modulated by cytokines to enhance CD36-mediated IRBC adhesion.

Quantitation of CD36 (platelet glycoprotein IV) expression on platelets and monocytes by flow cytometry: Application to the study of Plasmodium falciparum malaria

“…However, CD36 has been implicated as a key host ligand in the cytoadhesive virulence of P. falciparum malaria. Red blood cells infected with P. falciparum malaria erupt with an adhesive knob protein, P. falciparum erythrocyte membrane protein‐1 (PfEMP‐1), which binds with high affinity to CD36 (29–31). As a result, infected red cells not only sequester along the microvascular endothelium, bypassing splenic clearance, but also form rosettes with platelets through PfEMP‐1 interactions with platelet CD36.…”

“…As a result, infected red cells not only sequester along the microvascular endothelium, bypassing splenic clearance, but also form rosettes with platelets through PfEMP‐1 interactions with platelet CD36. In laboratory studies, CD36‐negative platelets do not form rosettes (32), and endothelial blockade of CD36 prevents most vascular sequestration (31).…”

Attenuation of Cytoadherence of Plasmodium Falciparum to Microvascular Endothelium Under Flow by Hemodilution

“…1 An understanding of the molecular basis of the adhesive process has evolved over the past decade. What was conceived and studied as a static interaction mediated by a single endothelial receptor [2][3][4][5][6][7] has now been shown to involve different types of dynamic adhesive interactions under physiologic flow conditions [8][9][10] that mimic the events involved in leukocyte recruitment. 11 Moreover, cytoadherence on microvascular endothelial cells is mediated synergistically by several adhesion molecules that appear to have different roles.…”

“…The IRBCs roll on intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P-selectin. 9 The low-affinity interactions with these molecules by themselves are not sufficient for the arrest of the rolling cells, but they enhance the subsequent adhesion of almost all clinical parasite isolates tested to CD36.…”

“…Cryopreserved parasite isolates from adult Thai patients with well-documented P. falciparum malaria were thawed and studied during the first cycle in culture as described. 9 Collection of infected blood was approved by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University (Bangkok, Thailand).…”