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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.


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Comparison of plasma concentration of haemoxygenase‐1 (HO‐1)at baseline and during malaria infection between both genotypical groups. Plasma concentration of HO‐1 was measured by enzyme‐linked immunosorbent assay (ELISA) in duplicate wells for each sample. Data are presented as scatter‐plots. Red line across indicates the mean, while error bars indicate standard error of the mean. Plasma concentration of HO‐1 did not differ at baseline (convalescence) between the two genotypes (P = 0·750 for AA versus AS at convalescence). Patients with the HbAA genotype had higher plasma concentration of HO‐1 compared with patients with HbAS genotype during malaria infection (*P < 0·001 for AA versus AS during acute malaria). Plasma concentration of HO‐1 increased significantly in patients with the HbAA genotype during malaria infection (**P < 0·001 for convalescence versus malaria), while it decreased in patients with the HbAS genotype during malaria infection (***P = 0·006 for convalescence versus malaria) (Student's t‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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cei12936-fig-0005: Comparison of plasma concentration of haemoxygenase‐1 (HO‐1)at baseline and during malaria infection between both genotypical groups. Plasma concentration of HO‐1 was measured by enzyme‐linked immunosorbent assay (ELISA) in duplicate wells for each sample. Data are presented as scatter‐plots. Red line across indicates the mean, while error bars indicate standard error of the mean. Plasma concentration of HO‐1 did not differ at baseline (convalescence) between the two genotypes (P = 0·750 for AA versus AS at convalescence). Patients with the HbAA genotype had higher plasma concentration of HO‐1 compared with patients with HbAS genotype during malaria infection (*P < 0·001 for AA versus AS during acute malaria). Plasma concentration of HO‐1 increased significantly in patients with the HbAA genotype during malaria infection (**P < 0·001 for convalescence versus malaria), while it decreased in patients with the HbAS genotype during malaria infection (***P = 0·006 for convalescence versus malaria) (Student's t‐test). [Colour figure can be viewed at wileyonlinelibrary.com]

Mentions: Increased induction of HO‐1 has been shown to control levels of haem 16; we consequently investigated whether higher baseline levels would be associated with the better control of haem that was observed in patients with the HbAS genotype during acute malaria. Levels of HO‐1 measured at convalescence were taken as predisease baseline levels. The concentration of circulating HO‐1 at convalescence did not differ significantly between the genotypes as quantified by ELISA (P = 0·750) (Fig. 5); however, levels of HO‐1 were significantly higher in the HbAA group compared with the HbAS group during malaria infection (P < 0·001) (Fig. 5). A significant increase in the induction of HO‐1 marked by an increased plasma concentration was observed in patients with the HbAA genotype during acute malaria compared with levels at convalescence (P < 0·001) (Fig. 5). In contrast, there was a significant decrease in the plasma concentration of HO‐1 in patients with the HbAS genotype during malaria infection compared with levels at convalescence (P = 0·006) (Fig. 5). As levels of HO‐1 did not differ significantly between genotypes at convalescence, we can infer that baseline levels of HO‐1 may not play a direct role in controlling haem levels during malaria infection in patients with the HbAS genotype.


Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection
Comparison of plasma concentration of haemoxygenase‐1 (HO‐1)at baseline and during malaria infection between both genotypical groups. Plasma concentration of HO‐1 was measured by enzyme‐linked immunosorbent assay (ELISA) in duplicate wells for each sample. Data are presented as scatter‐plots. Red line across indicates the mean, while error bars indicate standard error of the mean. Plasma concentration of HO‐1 did not differ at baseline (convalescence) between the two genotypes (P = 0·750 for AA versus AS at convalescence). Patients with the HbAA genotype had higher plasma concentration of HO‐1 compared with patients with HbAS genotype during malaria infection (*P < 0·001 for AA versus AS during acute malaria). Plasma concentration of HO‐1 increased significantly in patients with the HbAA genotype during malaria infection (**P < 0·001 for convalescence versus malaria), while it decreased in patients with the HbAS genotype during malaria infection (***P = 0·006 for convalescence versus malaria) (Student's t‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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Related In: Results  -  Collection

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cei12936-fig-0005: Comparison of plasma concentration of haemoxygenase‐1 (HO‐1)at baseline and during malaria infection between both genotypical groups. Plasma concentration of HO‐1 was measured by enzyme‐linked immunosorbent assay (ELISA) in duplicate wells for each sample. Data are presented as scatter‐plots. Red line across indicates the mean, while error bars indicate standard error of the mean. Plasma concentration of HO‐1 did not differ at baseline (convalescence) between the two genotypes (P = 0·750 for AA versus AS at convalescence). Patients with the HbAA genotype had higher plasma concentration of HO‐1 compared with patients with HbAS genotype during malaria infection (*P < 0·001 for AA versus AS during acute malaria). Plasma concentration of HO‐1 increased significantly in patients with the HbAA genotype during malaria infection (**P < 0·001 for convalescence versus malaria), while it decreased in patients with the HbAS genotype during malaria infection (***P = 0·006 for convalescence versus malaria) (Student's t‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
Mentions: Increased induction of HO‐1 has been shown to control levels of haem 16; we consequently investigated whether higher baseline levels would be associated with the better control of haem that was observed in patients with the HbAS genotype during acute malaria. Levels of HO‐1 measured at convalescence were taken as predisease baseline levels. The concentration of circulating HO‐1 at convalescence did not differ significantly between the genotypes as quantified by ELISA (P = 0·750) (Fig. 5); however, levels of HO‐1 were significantly higher in the HbAA group compared with the HbAS group during malaria infection (P < 0·001) (Fig. 5). A significant increase in the induction of HO‐1 marked by an increased plasma concentration was observed in patients with the HbAA genotype during acute malaria compared with levels at convalescence (P < 0·001) (Fig. 5). In contrast, there was a significant decrease in the plasma concentration of HO‐1 in patients with the HbAS genotype during malaria infection compared with levels at convalescence (P = 0·006) (Fig. 5). As levels of HO‐1 did not differ significantly between genotypes at convalescence, we can infer that baseline levels of HO‐1 may not play a direct role in controlling haem levels during malaria infection in patients with the HbAS genotype.

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