Abstract
Cerebral malaria (CM) presents as an encephalopathy and is due to infection with Plasmodium falciparum. Patients are comatose, often with fever, recurrent seizures and this condition is associated with a high mortality rate. The etiology of the coma and seizures are poorly understood. Circulating small molecules and lipids have bioactive functions and alterations in their concentrations have been implicated in seizure disorders and other forms of encephalopathy. We carried out a comprehensive analysis of blood metabolites during CM to explore a biochemical basis of this encephalopathy. A paired metabolomics analysis was performed on the plasma samples of Malawian children (n = 11) during CM and at convalescence thirty days later, to identify differentially abundant molecules associated with CM. We also report plasma molecules associated with CM mortality (n = 4) compared to survival (n = 19). Plasma metabolites were identified through ultra high performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry to maximize compound detection and accuracy and then compared to a library for identification. We detected a total of 432 small molecules in the plasma and 247 metabolites were significantly differentially abundant between CM and convalescence (p < 0.05, FDR < 0.10). These represented global changes across many classes of molecules including lipids, amino acids and hemoglobin metabolites. We observed significant changes in molecules that could impact neurologic function during CM; these include increased levels of kynurenate and decreased indolepropionate, glutamate, arginine and glutamine. Moreover, 1-methylimidazoleacetate, kyurenate, arachidonic acid and dimethylarginine were associated with mortality (p < 0.05, fold change > 1.2). These results highlight the broad changes in blood chemistry during CM. We have identified metabolites that may impact central nervous system physiology and disease outcomes and can be further explored for their mechanistic roles into the pathophysiology of CM.
Highlights
Despite improvements in clinical care and vector control, Plasmodium falciparum malaria remains a disease of global importance, with 214 million cases worldwide and 438,000 deaths, mostly among children in Africa [1]
Study subjects were Malawian children aged 6 months to 12 years enrolled in the Blantyre Malaria Project (BMP), who presented with Cerebral malaria (CM) during the malaria transmission season January through June 2013 [5, 6]
We identified greater than two hundred small molecules and lipids that were significantly altered during pediatric CM reflecting global blood chemistry dysregulation
Summary
Despite improvements in clinical care and vector control, Plasmodium falciparum malaria remains a disease of global importance, with 214 million cases worldwide and 438,000 deaths, mostly among children in Africa [1]. Cerebral malaria (CM), a severe complication of P. falciparum infection is heralded by coma, and a high prevalence of recurrent seizures and status epilepticus [2]. Metabolic changes in blood are common during CM and include hypoglycemia and hyperlactatemia, though a comprehensive analysis has not been reported [4]. Changes in blood composition reflect the physiology of a severe P. falciparum infection which is associated with high levels of inflammation, hemolysis and the presence of parasite derived metabolites. To examine the potential role of small molecules and lipids in the clinical findings of CM we carried out a comprehensive, unbiased plasma metabolomics association study in a cohort of Malawian children with CM during coma and during a convalescent state thirty days later
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