Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria: association with disease severity

PLoS Pathogens
Matthew RubachDonald L Granger

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 C...Continue Reading

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Citations

Oct 7, 2015·New Microbes and New Infections·C Akoua-KoffiS L Becker
Sep 20, 2016·ACS Infectious Diseases·Matthew S Alkaitis, Hans C Ackerman
Feb 13, 2019·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Tsin W YeoNicholas M Anstey
Dec 17, 2019·Immunological Reviews·Katherine R DobbsArlene E Dent
Feb 28, 2020·The Journal of Antimicrobial Chemotherapy·Domingos Magno Santos PereiraElizabeth Soares Fernandes
May 1, 2019·Scientific Reports·Stije J LeopoldArjen M Dondorp
Oct 30, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tsin W YeoJ Brice Weinberg
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Nov 7, 2019·The Journal of Infectious Diseases·Hugh W F KingstonArjen M Dondorp
Jul 5, 2017·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Sophie YacoubBridget Wills
Feb 23, 2021·The Journal of Infectious Diseases·Matthew P RubachDonald L Granger

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Methods Mentioned

BETA
urine collection
ELISA
PCR
ion-exchange chromatography
Fluorescence

Software Mentioned

EZ Chrom
STATA

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