Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity

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dc.contributor.authorMwaikambo, Esther D.
dc.date.accessioned2020-02-17T12:10:38Z
dc.date.available2020-02-17T12:10:38Z
dc.date.issued2015
dc.description.abstractDecreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH4 would be decreased in children with cerebral malaria, contributing to low NO bioavailability. In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states (fully reduced [BH4] and the oxidized metabolites, dihydrobiopterin [BH2] and biopterin [B0]) in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 45), non-malaria central nervous system conditions (NMC, n = 48), and in 111 healthy controls (HC). Median urine BH4 concentration in CM (1.10 [IQR:0.55–2.18] μmol/mmol creatinine) was significantly lower compared to each of the other three groups — UM (2.10 [IQR:1.32–3.14]; p<0.001), NMC (1.52 [IQR:1.01–2.71];p = 0.002), and HC (1.60 [IQR:1.15–2.23];p = 0.005). Oxidized biopterins were increased, and the BH4:BH2 ratio markedly decreased in CM. In a multivariate logistic regression model, each Log10-unit decrease in urine BH4 was independently associated with a 3.85-fold (95% CI:1.89–7.61) increase in odds of CM (p<0.001). Low systemic BH4 levels and increased oxidized biopterins contribute to the low NO bioavailability observed in CM. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.en_US
dc.description.sponsorshipNational Institutes of Health Fogarty International Center Global Health Fellowship the Veterans AffairsResearch Service Australian NHMRC Fellowshipsen_US
dc.identifier.citationRubach, M.P., Jackson Mukemba, S.F., Lopansri, B.K., Hyland, K., Volkheimer, A.D., Yeo, T.W., Anstey, N.M., Weinberg, J.B., Mwaikambo, E.D. and Granger, D.L., 2015. Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity. PLoS pathogens.en_US
dc.identifier.otherDOI:10.1371/journal.ppat.1004655
dc.identifier.urihttp://hdl.handle.net/123456789/238
dc.language.isoenen_US
dc.publisherPLoS pathogensen_US
dc.subjectOxidized Biopterinsen_US
dc.subjectPlasmodium falciparumen_US
dc.subjectTetrahydrobiopterinen_US
dc.titleImpaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severityen_US
dc.typeArticleen_US

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