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

PLoS Pathogens

Tsin W. Yeo¹  Matthew P. Rubach¹  Bert K. Lopansri²  Esther D. Mwaikambo³  Keith Hyland⁴  Jackson Mukemba⁵  Salvatore Florence⁵  J. Brice Weinberg⁶  Donald L. Granger⁷  Nicholas M. Anstey⁷  Alicia D. Volkheimer⁸ 

[1] Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina, United States of America;Department of Medicine, Intermountain Healthcare, Salt Lake City, Utah, United States of America;Department of Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;Department of Medicine, University of Utah School of Medicine and VA Medical Center, Salt Lake City, Utah, United States of America;Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania;Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia;Global and Tropical Health Division, Menzies School for Health Research and Charles Darwin University, Darwin, Australia;Neurochemistry Division, Medical Neurogenetics, Atlanta, Georgia, United States of America

关键词: Cerebral malaria;    Urine;    Malaria;    Nitric oxide;    Creatinine;    Phenylalanine;    Blood plasma;    Central nervous system;   

DOI  :  10.1371/journal.ppat.1004655

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY