Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection

Abstract

SummaryThe controlled induction of haemoxygenase‐1 (HO‐1), an enzyme that catabolizes haem, has been shown to reduce haem, preventing pathologies associated with haem toxicity. The hemoglobin genotype HbAS confers reduced susceptibility to severe complications of malaria by a mechanism that is not well understood. Using a longitudinal approach, we investigated the effect of baseline concentrations of HO‐1 on the accumulation of haem during acute Plasmodium falciparum malaria in HbAS and HbAA genotypes. Plasma concentrations of haem, HO‐1 and cytokines were quantified in venous blood obtained from children (9 months–5 years of age) during malaria infection, and at convalescence (baseline levels). Parasitaemia was determined during malaria infection. In patients with the HbAA genotype, there was a significant elevation in the plasma concentration of haem (P = 0.002), and a consequent increased induction of HO‐1 (P < 0.001) during falciparum malaria compared with levels at convalescence. Contrary to HbAA, plasma concentration of haem did not change in the HbAS genotypical group (P = 0·110), and the induction of HO‐1 was reduced during malaria compared with levels at convalescence (P = 0·006). Higher plasma levels of haem were observed in HbAS compared with HbAA at convalescence (P = 0·010), but this difference did not affect the levels of HO‐1 within each genotype (P = 0·450). Relatively milder proinflammatory responses were observed in HbAS children during malaria infection compared to HbAA children. Our findings suggest that a mechanism of reduced susceptibility to severe malaria pathologies by the HbAS genotype may involve the control of haem, leading to controlled levels of HO‐1 and milder proinflammatory responses during acute malaria.

Acute Phase Responses Vary Between Children of HbAS and HbAA Genotypes During Plasmodium falciparum Infection

“…A previous study by Ademoule et al that compared pro-inflammatory cytokines levels between HbAA and HbAS children also provides evidence that there is a higher inflammatory response in HbAA than in HbAS children during malaria. 21 …”

“…A previous study by Ademoule et al that compared pro-inflammatory cytokines levels between HbAA and HbAS children also provides evidence that there is a higher inflammatory response in HbAA than in HbAS children during malaria. 21 There are reports that higher or elevated levels of C-reactive protein attenuate the production of Nitric Oxide (NO), a potent anti-malarial, [23][24][25][26] achieved through downregulation of endothelial NO synthase (eNOS) transcription in Endothelial Cells (ECs) and destabilization of eNOS mRNA, with resultant decreases in basal and stimulated NO release. 26 Hence, with the observed disproportionate significant increase in the CRP levels in the HbAA children during P. falciparum infection, this might lead to differentially lower bioavailability of NO in HbAA than in HbAS individuals during malaria, with a resultant lower NO-mediated parasite clearance in them than in the HbAS.…”

“…Concurrently with the blood films, slides were prepared from each participant for a metabisulphite screening test and the Hb phenotype of children with positive sickling metabisulphite test were further determined using Hb electrophoresis. 21 …”

Cross sectional study on prevalence of sickle cell alleles S and C among patients with mild malaria in Ivory Coast

“…In Ghana, multivariate regression analysis showed that children with the AS genotype had 79% lower risk of malaria infection compared to those with the AA genotypes [ 14 , 17 ]. However this is still debating as in other studies no difference was found between people with and without trait [ 18 – 21 ]. The prevalence of CC genotype is also low in the malaria group.…”

Heme oxygenase-1 in protozoan infections: A tale of resistance and disease tolerance

“…falciparum infection. The control of heme concentrations during acute malaria infection was associated with a milder proinflammatory response in children with the HbAS genotype compared to the HbAA genotype [ 62 ]. Surprisingly, in this study the expression of HO-1 was not associated with the reduction of heme.…”