Targeting circulating labile heme as a defense strategy against malaria

Abstract

Severe presentations of malaria emerge asPlasmodium (P.) spp.parasites invade and lyse red blood cells (RBC), producing extracellular hemoglobin (HB), from which labile heme is released. Here, we tested whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, counter the pathogenesis of severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral presentations of severeP. falciparummalaria in children. Labile heme was negatively correlated with circulating HP and HPX, which were, however, not risk factors for severeP. falciparummalaria. GeneticHpand/orHpxdeletion in mice led to labile heme accumulation in plasma and kidneys, uponPlasmodium infection. This was associated with higher incidence of mortality and acute kidney injury (AKI) in ageing but not adultPlasmodium-infected mice, and was corroborated by an inverse correlation between heme and HPX with serological markers of AKI inP. falciparummalaria. In conclusion, HP and HPX act in an age-dependent manner to prevent the pathogenesis of severe presentation of malaria in mice and presumably in humans.