title: Pathophysiology of cerebral malaria: role of host cells in the modulation of cytoadhesion.
abstract: Cerebral malaria (CM), one of the most serious complications of Plasmodium falciparum infection, is characterized by the sequestration of infected erythrocytes (IEs) in cerebral microvascular beds. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances, and host immune responses all play a role. Studies in a murine model of CM showed a potential role for host cells, especially platelets, in the pathogenesis of CM. Indeed, urokinase plasminogen activator receptor (uPAR; CD87) deficiency attenuates the severity of CM, most likely by its important role in platelet kinetics and trapping. These results led us to evaluate whether platelets have a role in the human disease. By immunostaining of brain samples from Malawian patients, we determined that the surface of platelet accumulation and the proportion of vessels filled with platelets were significantly higher in patients who died of CM than in those who died of other causes. We then investigated the role of platelets in IE cytoadhesion in vitro, using CD36-binding IE (IECD36) and CD36-deficient (CD36DEF) brain microvascular endothelial cells (ECs). Coincubation studies indicated that platelets can induce strong IECD36 binding to CD36DEF ECs and, conversely, can hide constitutively expressed falciparum receptors such as chondroitin sulfate A. Thus, platelets may provide an adhesion receptor to microvascular beds originally devoid of it. This novel mechanism of cytoadhesion may reorient the sequestration of different parasite phenotypes and play an important role in the pathogenesis of severe malaria.
authors.affiliation: Unité de Parasitologie Expérimentale, EA 3282, IFR 48, Faculties of Medicine and Pharmacy, Université de la Méditerranée, F-13 385 Marseille Cedex 05, France.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wassmer
authors.forename: Valéry
authors.initials: V
authors.lastname: Combes
authors.forename: Georges E
authors.initials: GE
authors.lastname: Grau
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology; D001921:Brain / Q000469:parasitology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D008233:Lymphotoxin-alpha / Q000502:physiology; D016779:Malaria, Cerebral / Q000503:physiopathology*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I
chemical_list: D015703:Antigens, CD; D008233:Lymphotoxin-alpha; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I