RESUMEN
Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration.
Asunto(s)
Antígenos CD/metabolismo , Coagulación Sanguínea/fisiología , Encéfalo/parasitología , Endotelio Vascular/metabolismo , Inflamación , Malaria Cerebral/parasitología , Receptores de Superficie Celular/metabolismo , Antígenos CD/fisiología , Población Negra , Coagulación Sanguínea/inmunología , Encéfalo/irrigación sanguínea , Encéfalo/patología , Estudios de Casos y Controles , Niño , Preescolar , Regulación hacia Abajo , Receptor de Proteína C Endotelial , Eritrocitos/parasitología , Eritrocitos/patología , Femenino , Humanos , Lactante , Inflamación/metabolismo , Inflamación/parasitología , Malaria Cerebral/sangre , Malaria Cerebral/inmunología , Malaria Cerebral/metabolismo , Malaui , Masculino , Receptores de Superficie Celular/fisiología , Trombomodulina/metabolismo , Trombomodulina/fisiologíaRESUMEN
Endothelial dysregulation is central to the pathogenesis of acute Plasmodium falciparum infection. It has been assumed that this dysregulation resolves rapidly after treatment, but this return to normality has been neither demonstrated nor quantified. We therefore measured a panel of plasma endothelial markers acutely and in convalescence in Malawian children with uncomplicated or cerebral malaria. Evidence of persistent endothelial activation and inflammation, indicated by increased plasma levels of soluble intracellular adhesion molecule 1, angiopoetin 2, and C-reactive protein, were observed at 1 month follow-up visits. These vascular changes may represent a previously unrecognized contributor to ongoing malaria-associated morbidity and mortality.
Asunto(s)
Endotelio/patología , Malaria Cerebral/patología , Malaria Falciparum/patología , Análisis de Varianza , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Preescolar , Endotelio/metabolismo , Femenino , Fiebre/sangre , Fiebre/parasitología , Fiebre/patología , Humanos , Inflamación/sangre , Inflamación/parasitología , Inflamación/patología , Molécula 1 de Adhesión Intercelular/sangre , Malaria Cerebral/sangre , Malaria Falciparum/sangre , Malaui , Masculino , Proteínas de Transporte Vesicular/sangreRESUMEN
Sequestration of Plasmodium falciparum-infected erythrocytes (IE) within the brain microvasculature is a hallmark of cerebral malaria (CM). Using a microchannel flow adhesion assay with TNF-activated primary human microvascular endothelial cells, we demonstrate that IE isolated from Malawian paediatric CM cases showed increased binding to brain microvascular endothelial cells compared to IE from uncomplicated malaria (UM) cases. Further, UM isolates showed significantly greater adhesion to dermal than to brain microvascular endothelial cells. The major mediator of parasite adhesion is P. falciparum erythrocyte membrane protein 1, encoded by var genes. Higher levels of var gene transcripts predicted to bind host endothelial protein C receptor (EPCR) and ICAM-1 were detected in CM isolates. These data provide further evidence for differential tissue binding in severe and uncomplicated malaria syndromes, and give additional support to the hypothesis that CM pathology is based on increased cytoadherence of IE in the brain microvasculature.