Abstract
Background Malaria is associated with haemolysis and the release of plasma haem. Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypothesized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections.MethodsPlasma levels of haemin (oxidized haem), haemopexin, haptoglobin, and haemoglobin were quantified in a case–control study of Ugandan children with Plasmodium falciparum malaria. Levels at presentation were compared in children with uncomplicated malaria (UM; n = 29), severe malarial anaemia (SMA; n = 27) or cerebral malaria (CM; n = 31), and evaluated for utility in predicting fatal (n = 19) vs non-fatal (n = 39) outcomes in severe disease. A causal role for haemopexin was assessed in a pre-clinical model of experimental cerebral malaria (ECM), following disruption of mouse haemopexin gene (hpx). Analysis was done using Kruskall Wallis tests, Mann–Whitney tests, log-rank tests for survival, and repeated measures ANOVA.ResultsIn Ugandan children presenting with P. falciparum malaria, haemin levels were higher and haemopexin levels were lower in SMA and CM compared to children with UM (haemin, p < 0.01; haemopexin, p < 0.0001). Among all cases of severe malaria, elevated levels of haemin and cell-free haemoglobin at presentation were associated with subsequent mortality (p < 0.05). Compared to ECM-resistant BALB/c mice, susceptible C57BL/6 mice had lower circulating levels of haemopexin (p < 0.01), and targeted deletion of the haemopexin gene, hpx, resulted in increased mortality compared to their wild type littermates (p < 0.05).ConclusionsThese data indicate that plasma levels of haemin and haemopexin measured at presentation correlate with malaria severity and levels of haemin and cell-free haemoglobin predict outcome in paediatric severe malaria. Mechanistic studies in the ECM model support a causal role for the haem-haemopexin axis in ECM pathobiology.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-1028-1) contains supplementary material, which is available to authorized users.
Highlights
Malaria is associated with haemolysis and the release of plasma haem
Children were eligible for enrolment in this study if they met WHO criteria for severe malarial anaemia (SMA) (Hb 3 seizures witnessed within a 24-hour period; and, absence of hypoglycemia (7.0 g/dL, platelet count >100,000/ uL, with absence of hypoxia, lactic acidosis, respiratory distress, seizures, and coma); and, had a pre-treatment plasma sample collected at presentation and stored frozen until analysis
This study provides evidence that increased generation of plasma haem, combined with lower levels of haemopexin that normally binds and clears haem, are associated with both SMA and CM in Ugandan a b
Summary
Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypoth‐ esized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections. In conditions of intravascular haemolysis these protective pathways may be overwhelmed resulting in oxidative stress, reduced nitric oxide bioavailability, inflammation, endothelial activation, and platelet/fibrin microthrombi that together culminate in vascular dysfunction and multi-organ injury. Using a case–control study the association of the haem axis with severe and fatal malaria in African children was investigated. These investigations were extended to explore a potential mechanistic role for haemopexin using a pre-clinical animal model
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