Targeting circulating labile heme as a defense strategy against malaria

Abstract

Severe presentations of malaria emerge as <i>Plasmodium (P.) spp.</i> 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 severe <i>P. falciparum</i> malaria in children. Labile heme was negatively correlated with circulating HP and HPX, which were, however, not risk factors for severe <i>P. falciparum</i> malaria. Genetic <i>Hp</i> and/or <i>Hpx</i> deletion in mice led to labile heme accumulation in plasma and kidneys, upon <i>Plasmodium infection</i> This was associated with higher incidence of mortality and acute kidney injury (AKI) in ageing but not adult <i>Plasmodium</i>-infected mice, and was corroborated by an inverse correlation between heme and HPX with serological markers of AKI in <i>P. falciparum</i> malaria. 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.