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Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium

Dorothée Faille^*,, Valéry Combes^*, Andrew J. Mitchell, Albin Fontaine, Irène Juhan-Vague, Marie-Christine Alessi, Giovanna Chimini, Thierry Fusaï and Georges E. Grau^*,1

^* Department of Pathology, University of Sydney, Camperdown, Australia;

Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France; and

Centre d’Immunologie Marseille-Luminy, INSERM U631, Centre National de la Recherche Scientifique UMR6102, Faculté des Sciences, and

INSERM U626, Faculté de Médecine, Aix-Marseille Université, Marseille, France

¹ Correspondence: Department of Pathology, Faculty of Medicine, University of Sydney, Medical Foundation Bldg. (K25), Rm. 208, 92-94 Parramatta Rd, Camperdown, NSW 2042, Australia. E-mail: ggrau{at}med.usyd.edu.au

Cerebral malaria (CM) is characterized by accumulation of circulating cells within brain microvessels, among which platelets play an important role. In vitro, platelets modulate the cytoadherence of Plasmodium falciparum-parasitized red blood cells (PRBCs) to brain endothelial cells. Here we show for the first time that platelet microparticles (PMPs) are able to bind to PRBCs, thereby transferring platelet antigens to the PRBC surface. This binding is largely specific to PRBCs, because PMPs show little adherence to normal red blood cells. PMP adherence is also dependent on the P. falciparum erythrocyte membrane protein 1 variant expressed by PRBCs. PMP binding to PRBCs decreases after neutralization of PRBC surface proteins by trypsin or after treatment of PMPs with a mAb to platelet-endothelial cell adhesion molecule-1 (CD31) and glycoprotein IV (CD36). Furthermore, PMP uptake is a dynamic process that can be achieved by human brain endothelial cells (HBECs), inducing changes in the endothelial phenotype. Lastly, PMPs dramatically increase PRBC cytoadherence to HBECs. In conclusion, our study identifies several mechanisms by which PMPs may participate in CM pathogenesis while interacting with both PRBCs and HBECs. PMPs thereby provide a novel target for antagonizing interactions between vascular cells that promote microvascular sludging and blood brain barrier alteration during CM.—Faille, D., Combes, V., Mitchell, A. J., Fontaine, A., Juhan-Vague, I., Alessi, M.-C., Chimini, G., Fusaï, T., Grau, G. E. Platelet microparticles: a new player in malaria parasite cytoadherence to human brain endothelium.

Key Words: vesiculation • internalization • antigen transfer • microvessels • pathogenesis • neuroinflammation