Abstract
BackgroundCerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection. A number of pathological findings have been correlated with pediatric CM including sequestration, platelet accumulation, petechial haemorrhage and retinopathy. However, the molecular mechanisms leading to death in CM are not yet fully understood.MethodsA shotgun plasma proteomic study was conducted using samples form 52 Gambian children with CM admitted to hospital. Based on clinical outcome, children were assigned to two groups: reversible and fatal CM. Label-free liquid chromatography–tandem mass spectrometry was used to identify and compare plasma proteins that were differentially regulated in children who recovered from CM and those who died. Candidate biomarkers were validated using enzyme immunoassays.ResultsThe plasma proteomic signature of children with CM identified 266 proteins differentially regulated in children with fatal CM. Proteins from the coagulation cascade were consistently decreased in fatal CM, whereas the plasma proteomic signature associated with fatal CM underscored the importance of endothelial activation, tissue damage, inflammation, haemolysis and glucose metabolism. The concentration of circulating proteasomes or PSMB9 in plasma was not significantly different in fatal CM when compared with survivors. Plasma PSMB9 concentration was higher in patients who presented with seizures and was significantly correlated with the number of seizures observed in patients with CM during admission.ConclusionsThe results indicate that increased tissue damage and hypercoagulability may play an important role in fatal CM. The diagnostic value of this molecular signature to identify children at high risk of dying to optimize patient referral practices should be validated prospectively.
Highlights
Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection
Clinical study EDTA-plasma samples were collected from children aged 4 months to 14 years admitted to the Royal Victoria Teaching Hospital (RVTH) in Banjul, the main health facility in The Gambia, from January 1997 to December 2009 [23]
All patients included in the study had a blood smear positive for asexual P. falciparum parasites and met one or more of the WHO criteria for severe malaria [19]
Summary
Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection. The molecular mechanisms leading to death in CM are not yet fully understood. Severe malaria (SM) is a major public health problem that accounts for more than 400,000 deaths each year, mainly in sub-Saharan Africa [1]. Cerebral malaria (CM) is a severe neurological complication of malaria infection that causes acute non-traumatic encephalopathy. Children with CM usually present with coma and 1–4 days history of fever and convulsions [2]. In African children, The pathophysiology of CM is poorly understood and several mechanisms of disease have been proposed [5]. Parasite sequestration and cytokine activation are the two leading hypotheses to explain CM pathogenesis [2, 6]. Sequestration of parasite-infected erythrocytes (PfIEs) obstructs brain microvasculature
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