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.
Original language | English |
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Article number | e1004655 |
Pages (from-to) | 1-22 |
Number of pages | 22 |
Journal | PLoS Pathogens |
Volume | 11 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2015 |