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

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ABSTRACT

The 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.

No MeSH data available.


Related in: MedlinePlus

Comparison of parasite densities between both genotypic groups. Parasitaemia was determined by microscopy from Giemsa‐stained thick smears. Data are presented as scatter‐plots. The red line across indicates median value (P = 0·467, Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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cei12936-fig-0002: Comparison of parasite densities between both genotypic groups. Parasitaemia was determined by microscopy from Giemsa‐stained thick smears. Data are presented as scatter‐plots. The red line across indicates median value (P = 0·467, Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]

Mentions: One hundred and forty children who were referred for malaria tests by the attending physician were recruited into the study. The proportions of the various haemoglobin genotypes were HbAA = 66%, HbAS = 25%, HbAC = 5%, HbSC < 1% and HbSS < 4% in the entire population. Samples from children with the HbSS, HbAC and HbSC genotypes were excluded from other analyses due to very low numbers. From the total recruited children, 62 tested positive to malaria including 26 (40%) males and 36 (60%) females, with a mean age of 36 (range = 9–96) months. There were no significant differences in age (P = 0·200) and gender (P = 0·740) when they were stratified based on haemoglobin genotypes (i.e. HbAS and HbAA). Forty children with either HbAS or HbAA genotype were found to be parasite‐free by microscopy 3 weeks later (HbAS, n = 21; HbAA, n = 19). Among children with malaria, parasite density did not differ significantly between genotypes (P = 0·467) (Fig. 2).


Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection
Comparison of parasite densities between both genotypic groups. Parasitaemia was determined by microscopy from Giemsa‐stained thick smears. Data are presented as scatter‐plots. The red line across indicates median value (P = 0·467, Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383446&req=5

cei12936-fig-0002: Comparison of parasite densities between both genotypic groups. Parasitaemia was determined by microscopy from Giemsa‐stained thick smears. Data are presented as scatter‐plots. The red line across indicates median value (P = 0·467, Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
Mentions: One hundred and forty children who were referred for malaria tests by the attending physician were recruited into the study. The proportions of the various haemoglobin genotypes were HbAA = 66%, HbAS = 25%, HbAC = 5%, HbSC < 1% and HbSS < 4% in the entire population. Samples from children with the HbSS, HbAC and HbSC genotypes were excluded from other analyses due to very low numbers. From the total recruited children, 62 tested positive to malaria including 26 (40%) males and 36 (60%) females, with a mean age of 36 (range = 9–96) months. There were no significant differences in age (P = 0·200) and gender (P = 0·740) when they were stratified based on haemoglobin genotypes (i.e. HbAS and HbAA). Forty children with either HbAS or HbAA genotype were found to be parasite‐free by microscopy 3 weeks later (HbAS, n = 21; HbAA, n = 19). Among children with malaria, parasite density did not differ significantly between genotypes (P = 0·467) (Fig. 2).

View Article: PubMed Central - PubMed

ABSTRACT

The controlled induction of haemoxygenase&#8208;1 (HO&#8208;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&#8208;1 on the accumulation of haem during acute Plasmodium falciparum malaria in HbAS and HbAA genotypes. Plasma concentrations of haem, HO&#8208;1 and cytokines were quantified in venous blood obtained from children (9 months&ndash;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&thinsp;=&thinsp;0.002), and a consequent increased induction of HO&#8208;1 (P&thinsp;&lt;&thinsp;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&thinsp;=&thinsp;0&middot;110), and the induction of HO&#8208;1 was reduced during malaria compared with levels at convalescence (P&thinsp;=&thinsp;0&middot;006). Higher plasma levels of haem were observed in HbAS compared with HbAA at convalescence (P&thinsp;=&thinsp;0&middot;010), but this difference did not affect the levels of HO&#8208;1 within each genotype (P&thinsp;=&thinsp;0&middot;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&#8208;1 and milder proinflammatory responses during acute malaria.

No MeSH data available.


Related in: MedlinePlus