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Published on: January 16, 2015
Age-dependent effect of plasma nitric oxide on parasite density in Ghanaian children with severe malaria
Jakob P Cramer1, Andreas K Nüssler, Stephan Ehrhardt
1Institute of Tropical Medicine Berlin, Charité- University Medicine Berlin, Germany. jakob.cramer@charite.de
Insights
High nitric oxide (NO) metabolites in young children with severe malaria correlate with reduced parasite density. This protective effect diminishes with age, suggesting age-dependent immune responses influence malaria outcomes.
Area of Science:
- Immunology
- Genetics
- Malariology
Background:
- Nitric oxide (NO) exhibits toxicity against Plasmodium falciparum.
- High NO blood levels are linked to both protection and pathogenesis in severe malaria, including cerebral malaria and severe anemia.
- Inducible nitric oxide synthase (iNOS) gene promoter variants are implicated in NO concentration and disease outcomes, but findings are inconsistent.
Purpose of the Study:
- To investigate the association between plasma nitric oxide metabolites (NOx) and severe malaria symptoms, specifically malarial anemia and cerebral malaria.
- To explore the relationship between NOx levels and iNOS gene promoter variants in Ghanaian children with severe malaria.
Main Methods:
- Plasma nitrite, nitrate, and S-nitrosothiol levels were measured in 210 Ghanaian children with severe malaria.
- Genotyping was performed for iNOS promoter variants: -954G-->C, -1173C-->T, and the -2.5 kb (CCTTT)(n) microsatellite.
- Statistical analyses examined correlations between NOx levels, iNOS genotypes, and clinical malaria manifestations.
Main Results:
- Plasma NOx levels decreased with increasing age.
- In children under 24 months, higher NOx levels were associated with reduced parasite density, an effect that reversed in older children.
- In severe anemia cases without cerebral malaria, elevated NOx correlated with lower parasitemia and was linked to the iNOS-954C-->T/(CCTTT)(8) haplotype.
- No significant association was found between NOx levels or iNOS genotypes and cerebral malaria.
Conclusions:
- In young children with severe malaria, nitric oxide metabolites appear to reduce parasite density, indicating a potential protective role.
- This NO-mediated antiparasitic effect wanes with age, possibly due to shifts in immune responses from specific to non-specific mechanisms.
- Understanding these age-dependent associations between iNOS variants and severe malaria is crucial for regions with varying disease manifestations.
Abstract:
Nitric oxide (NO) has toxic properties against Plasmodium falciparum. While high blood levels have been associated with protection against severe malarial disease, they may also contribute to the pathophysiology of cerebral malaria and severe anaemia. Promoter variants in the inducible nitric oxide synthase (iNOS) gene have been shown to influence NO concentrations and disease manifestation. However, findings are conflicting. We examined associations of plasma NO metabolites (NOx) with symptoms of severe malaria, particularly malarial anaemia and cerebral malaria, and with iNOS promoter variants. In 210 Ghanaian children with severe malaria, we measured plasma nitrite, nitrate, and S-nitrosothiol, and genotyped the iNOS promoter variants -954G-->C, -1173C-->T, and the -2.5 kb (CCTTT)(n) microsatellite. NOx levels decreased with age. In young children (<24 months), high NOx was associated with reduced parasite density. This was not seen in patients of 24-48 months of age and reversed in older children. Subgroup analysis revealed that in children with severe anaemia but without cerebral involvement (prostration, impaired consciousness, convulsions), high NOx levels correlated with low parasitaemia (P = 0.02). In these children, elevated NOx levels were also associated with the iNOS-954C-->T/(CCTTT)(8) haplotype (P = 0.03). No association between NOx or iNOS genotypes and cerebral malaria was observed. Our findings suggest that in young children with severe malaria NOx reduces parasitaemia. This effect wanes at higher ages and may reflect a predominance of unspecific immune responses to infection in early childhood. This finding may have importance for the understanding of associations between iNOS variants and severe malaria in regions of differing disease manifestation.
