Dependence of plasmodial glutathione metabolism on the host cell

Abstract

ONE inherited alteration of human red cell metabolism—quantitative deficiency of the X-linked enzyme glucose-6-phosphate dehydrogenase (G-6-PD)—has attained high frequency in many areas of endemic malaria and may protect against fulminant Plasmodium falciparum in some unknown fashion^1–5. G-6-PD catalyses the first step of the pentose phosphate pathway which provides reduced NADPH necessary for conversion of oxidised to reduced glutathione (GSSG→GSH)⁶. Erythrocytes deficient in G-6-PD are inefficient in generating NADPH and, when exposed to oxidants, lose GSH, accumulate oxidised haemoglobin and are destroyed by the reticuloendothelial system⁶. We hypothesised that, if the malaria parasite were to use red-cell NADPH for parasitic functions, the G-6-PD-deficient erythrocyte might be incapable of maintaining adequate GSH content. This would predispose the cell to premature destruction before the parasite matured, thereby limiting the severity of infection^7–9. In exploring this hypothesis, we have investigated factors affecting GSH metabolism in malaria-infected mouse erythrocytes. We find that P. berghei malaria may utilise host-cell NADPH for the maintenance of parasite GSH. These observations may help elucidate both the parasite-induced red cell oxidant damage⁷ and the mechanism whereby G-6-PD deficiency protects against fulminant malaria infection.