Rho kinase inhibition in severe malaria: thwarting parasite-induced collateral damage to endothelia.
Acute clinical manifestations of falciparum malaria, such as multiorgan failure and cerebral malaria, occur unpredictably and lead to coma and death within hours if left untreated. Despite the emergency administration of effective antimalarial drugs, 15%-20% of patients die. Other therapeutic approaches are therefore urgently needed. There is increasing evidence that endothelial changes play a key role in the pathogenesis of severe malaria. We therefore used coculture models to study interactions between infected erythrocytes and endothelium. We found that adhesion of Plasmodium falciparum to endothelial cells in vitro activated the Rho kinase signaling pathway, which is strongly involved in various vascular diseases. When added concomitantly with parasites, the Rho kinase inhibitor fasudil (HA-1077), a drug already in clinical use, decreased both NF-kappaB activation and endothelial cell apoptosis. Fasudil also helped to restore endothelial barrier integrity after P. falciparum adhesion. Rho kinase inhibition thus appears to be a promising adjunctive therapeutic approach to the management of severe human malaria.
Taoufiq
Zacharie
Z
Institut National de la Santé et de la Recherche Médicale Unité 511, Laboratoire d'Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Paris, France. zacharie.taoufiq@wanadoo.fr
Gay
Frederick
F
Balvanyos
Judith
J
Ciceron
Liliane
L
Tefit
Maurel
M
Lechat
Philippe
P
Mazier
Dominique
D
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000187:drug effects / Q000469:parasitology*; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010963:Plasmodium falciparum / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil