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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.

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Proinflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010; ***P < 0·001; ****P < 0·0001; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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cei12936-fig-0006: Proinflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010; ***P < 0·001; ****P < 0·0001; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]

Mentions: An excessive proinflammatory response has been implicated as a contributing factor to severe malaria pathologies 14, 29. As extracellular haem can activate immune cells and cause the excessive secretion of proinflammatory cytokines 30, 31, we investigated whether higher levels of haem that were observed in patients with the HbAA genotype were associated with an increased inflammatory response during malaria infection. As quantified by a multiplex assay, no significant increase in the plasma concentrations of IFN‐γ, IL‐12, IL‐2, IL‐1β and IL‐6 was observed in patients with the HbAS genotype during malaria infection compared with levels at convalescence (P = 0·620, P = 0·090, P = 0·150, P = 0·890 and P = 0·450, respectively) (Fig. 6a–e). However, levels of these proinflammatory cytokines increased significantly during malaria infection in patients with the HbAA genotype (P < 0·001, P < 0·001, P = 0·001, P = 0·045 and P < 0·001, respectively) (Fig. 6a–e). In addition, IFN‐γ levels were elevated significantly during malaria infection in patients with the HbAA genotype compared with the HbAS genotype (P = 0·008) (Fig. 6a). Levels of TNF‐α did not increase significantly within each genotype during malaria infection compared with baseline concentration (HbAA: P = 0·990; HbAS P = 0·740) (Fig. 6f). Taken together, this result suggests that children with the HbAS genotype are better able to control the proinflammatory response during acute malaria, presumably because they are better able to control levels of haem.


Sickle cell trait is associated with controlled levels of haem and mild proinflammatory response during acute malaria infection
Proinflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010; ***P < 0·001; ****P < 0·0001; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
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cei12936-fig-0006: Proinflammatory cytokine profile within each genotype during malaria infection. Data are presented as scatter‐plots. The line across represents the median value (*P < 0·050; **P < 0·010; ***P < 0·001; ****P < 0·0001; Mann–Whitney U‐test). [Colour figure can be viewed at wileyonlinelibrary.com]
Mentions: An excessive proinflammatory response has been implicated as a contributing factor to severe malaria pathologies 14, 29. As extracellular haem can activate immune cells and cause the excessive secretion of proinflammatory cytokines 30, 31, we investigated whether higher levels of haem that were observed in patients with the HbAA genotype were associated with an increased inflammatory response during malaria infection. As quantified by a multiplex assay, no significant increase in the plasma concentrations of IFN‐γ, IL‐12, IL‐2, IL‐1β and IL‐6 was observed in patients with the HbAS genotype during malaria infection compared with levels at convalescence (P = 0·620, P = 0·090, P = 0·150, P = 0·890 and P = 0·450, respectively) (Fig. 6a–e). However, levels of these proinflammatory cytokines increased significantly during malaria infection in patients with the HbAA genotype (P < 0·001, P < 0·001, P = 0·001, P = 0·045 and P < 0·001, respectively) (Fig. 6a–e). In addition, IFN‐γ levels were elevated significantly during malaria infection in patients with the HbAA genotype compared with the HbAS genotype (P = 0·008) (Fig. 6a). Levels of TNF‐α did not increase significantly within each genotype during malaria infection compared with baseline concentration (HbAA: P = 0·990; HbAS P = 0·740) (Fig. 6f). Taken together, this result suggests that children with the HbAS genotype are better able to control the proinflammatory response during acute malaria, presumably because they are better able to control levels of haem.

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