TY - JOUR
T1 - Age-dependent effect of plasma nitric oxide on parasite density in Ghanaian children with severe malaria
AU - Cramer, Jakob P.
AU - Nüssler, Andreas K.
AU - Ehrhardt, Stephan
AU - Burkhardt, Jana
AU - Otchwemah, Rowland N.
AU - Zanger, Philipp
AU - Dietz, Ekkehart
AU - Gellert, Sabine
AU - Bienzle, Ulrich
AU - Mockenhaupt, Frank P.
PY - 2005/7
Y1 - 2005/7
N2 - 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.
AB - 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.
KW - Nitric oxide
KW - Plasmodium falciparum
KW - Severe malaria
KW - iNOS promoter polymorphisms
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U2 - 10.1111/j.1365-3156.2005.01438.x
DO - 10.1111/j.1365-3156.2005.01438.x
M3 - Article
C2 - 15960706
AN - SCOPUS:21644454641
SN - 1360-2276
VL - 10
SP - 672
EP - 680
JO - Tropical Medicine and International Health
JF - Tropical Medicine and International Health
IS - 7
ER -