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

Rubach, Matthew P., Mukemba, Jackson, Florence, Salvatore, Lopansri, Bert K., Hyland, Keith, Volkheimer, Alicia D., Yeo, Tsin, Anstey, Nicholas M., Weinberg, J. Brice, Mwaikambo, Esther D. and Granger, Donald L. (2015). Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity. PLoS Pathogens,11(3 - Article No. e1004655).

Document type: Journal Article
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IRMA ID 75039815xPUB922
Title Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity
Author Rubach, Matthew P.
Mukemba, Jackson
Florence, Salvatore
Lopansri, Bert K.
Hyland, Keith
Volkheimer, Alicia D.
Yeo, Tsin
Anstey, Nicholas M.
Weinberg, J. Brice
Mwaikambo, Esther D.
Granger, Donald L.
Journal Name PLoS Pathogens
Publication Date 2015
Volume Number 11
Issue Number 3 - Article No. e1004655
ISSN 1553-7374   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-84926451936
Total Pages 22
Place of Publication United States of America
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DIISR)
Abstract Decreased 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.
DOI http://dx.doi.org/10.1371/journal.ppat.1004655   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
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