Targeting Circulating Labile Heme as a Defense Strategy Against Malaria
Severe presentations of malaria emerge as parasites from Plasmodium spp. proliferate and lyse red blood cells (RBC), producing extracellular hemoglobin (HB). The heme prosthetic groups are released upon HB oxidation generating circulating labile heme. Here we asked whether scavenging of extracellular HB and/or labile heme, by haptoglobin (HP) and/or hemopexin (HPX), respectively, is protective against severe presentations of malaria. We found that circulating labile heme is an independent risk factor for cerebral and non-cerebral severe presentations of P. falciparum malaria. Labile heme was negatively correlated with HP and HPX, which were however, not risk factors for severe P. falciparum malaria. Genetic HP and/or HPX deletion in mice led to accumulation of labile heme in plasma and kidneys in response to Plasmodium (chabaudi chabaudi) infection. This was associated with increased mortality and acute kidney injury (AKI) in ageing but not adult mice, corroborated in P. falciparum malaria by a an inverse correlation between HPX and heme with serological markers of AKI. In conclusion, HP and HPX exert an age-dependent protective effect against malaria that counters the pathogenesis of AKI in mice and presumably in humans. Overall design: Goal: To assess transcriptional differences in the kidney imposed by the lack of heme- and hemoglobin scavenging proteins Hemopexin (Hpx) and Haptoglobin (Hp), respectively, during malaria, as well as transcriptional differences in the kidney that are associated with ageing, within the same context of malaria and Hp/Hpx double knock-out mice. Procedure: We performed Next Generation Sequencing of kidney samples harvested from control (Hp+/+Hpx+/+) and hemopexin/haptoglobin double knock-out (Hp-/-Hpx-/-) C57BL/6 mice infected or not with Plasmodium chabaudi chabaudi (Pcc) at 9 weeks and 7 months of age (Samples collected on day 7 post-infection). We performed comparative analysis of gene expression between Pcc-infected adult (9 weeks old) and ageing (7 months old) mice, as well as between infected and uninfected control and Hp-/-Hpx-/- double knock-out mice.