title: Age-dependent effect of plasma nitric oxide on parasite density in Ghanaian children with severe malaria.
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.
authors.affiliation: Institute of Tropical Medicine Berlin, Charité- University Medicine Berlin, Germany. jakob.cramer@charite.de
authors.forename: Jakob P
authors.initials: JP
authors.lastname: Cramer
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nüssler
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehrhardt
authors.forename: Jana
authors.initials: J
authors.lastname: Burkhardt
authors.forename: Rowland N
authors.initials: RN
authors.lastname: Otchwemah
authors.forename: Philipp
authors.initials: P
authors.lastname: Zanger
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Dietz
authors.forename: Sabine
authors.initials: S
authors.lastname: Gellert
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bienzle
authors.forename: Frank P
authors.initials: FP
authors.lastname: Mockenhaupt
mesh_terms: D000367:Age Factors; D000740:Anemia / Q000097:blood / Q000469:parasitology; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000097:blood / Q000469:parasitology; D016778:Malaria, Falciparum / Q000097:blood / Q000453:epidemiology / Q000469:parasitology*; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000097:blood; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010270:Parasite Egg Count; D010963:Plasmodium falciparum / Q000302:isolation & purification; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D026403:S-Nitrosothiols / Q000097:blood
chemical_list: D009566:Nitrates; D009573:Nitrites; D026403:S-Nitrosothiols; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II