title: Metabolic acidosis induced by Plasmodium falciparum intraerythrocytic stages alters blood-brain barrier integrity.
abstract: The pathogenesis of cerebral malaria (CM) remains largely unknown. There is growing evidence that combination of both parasite and host factors could be involved in blood-brain barrier (BBB) breakdown. However, lack of adequate in vitro model of human BBB so far hampered molecular studies. In this article, we propose the use of hCMEC/D3 cells, a well-established human cerebral microvascular endothelial cell (EC) line, to study BBB breakdown induced by Plasmodium falciparum-parasitized red blood cells and environmental conditions. We show that coculture of parasitized erythrocytes with hCMEC/D3 cells induces cell adhesion and paracellular permeability increase, which correlates with disorganization of zonula occludens protein 1 expression pattern. Permeability increase and modification of tight junction proteins distribution are cytoadhesion independent. Finally, we show that permeability of hCMEC/D3 cell monolayers is mediated through parasite induced metabolic acidosis, which in turns correlates with apoptosis of parasitized erythrocytes. This new coculture model represents a very useful tool, which will improve the knowledge of BBB breakdown and the development of adjuvant therapies, together with antiparasitic drugs.
authors.affiliation: INSERM, UMRS 945, Paris, France.
authors.forename: Sergine
authors.initials: S
authors.lastname: Zougbédé
authors.forename: Florence
authors.initials: F
authors.lastname: Miller
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.forename: Angelita
authors.initials: A
authors.lastname: Rebollo
authors.forename: Liliane
authors.initials: L
authors.lastname: Cicéron
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno
mesh_terms: D000138:Acidosis / Q000378:metabolism* / Q000469:parasitology*; D017304:Annexin A5 / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000469:parasitology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology*; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D016779:Malaria, Cerebral / Q000097:blood* / Q000469:parasitology*; D016778:Malaria, Falciparum / Q000097:blood* / Q000469:parasitology*; D052940:Merozoites / Q000469:parasitology / Q000502:physiology; D018613:Microscopy, Confocal; D010539:Permeability; D010963:Plasmodium falciparum; D034622:RNA Interference; D019108:Tight Junctions / Q000378:metabolism; D014161:Transduction, Genetic; D014357:Trypsin / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D007770:L-Lactate Dehydrogenase; D014357:Trypsin