Blood-brain barrier breakdown during cerebral malaria: suicide or murder?
Cerebral malaria, one of the most serious complications of Plasmodium falciparum infection, is characterized by the sequestration of parasitized red blood cells (PRBCs) 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. Sequestration of PRBCs is mediated by different endothelial cell surface receptors, mainly ICAM-1 and CD36. In vitro studies demonstrated that PRBC adhesion to endothelial cells induces over-expression of various adhesion molecules including ICAM-1, expression of iNOS, oxidative stress and finally apoptosis in endothelial cells. In vivo studies, in humans and in mice models of cerebral malaria brought striking evidence of the implication of brain infiltrating cytotoxic effector CD8T lymphocytes in the development of murine cerebral malaria pathogenesis. These cells probably act by direct cytotoxicity against endothelial cells. Cytotoxicity and apoptosis potentially lead blood-brain-barrier disruption and could contribute to the development of cerebral malaria. We propose a key role for endothelial cells in the pathogenesis of cerebral malaria, both by suicide / apoptosis, and / or by murder / cytotoxicity.
Pino
Paco
P
INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Paris, France.
Taoufiq
Zacharie
Z
Nitcheu
Josiane
J
Vouldoukis
Ioanis
I
Mazier
Dominique
D
D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D018955:CD36 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D004912:Erythrocytes / Q000469:parasitology* / Q000648:ultrastructure; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016779:Malaria, Cerebral / Q000469:parasitology* / Q000503:physiopathology*; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress; D010587:Phagocytosis
D018955:CD36 Antigens; D015815:Cell Adhesion Molecules; D018799:Intercellular Adhesion Molecule-1