Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation
Year: 2015
Type: article
Study design: Observational Study
Abstract: Tetrahydrobiopterin (BH₄) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH₂), which inhibits NOS. Depending on BH₄ availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH₄/BH₂ ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH₄ deficiency. The primary three biopterin metabolites (BH₄, BH₂ and B₀ [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH₄ was decreased (median 0.16 ¼mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH₂ was increased in SM (median 0.91 ¼mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH₄/BH₂ ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH₄/BH₂ ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH₂ in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.
Source: PLoS Pathogens
Institutions: Nanyang Technological University, Tan Tock Seng Hospital, Charles Darwin University, Menzies School of Health Research, Kementerian Kesehatan Republik Indonesia, University of Oxford, Duke University, Duke Medical Center, University of Utah, Veterans Health Administration, VA Salt Lake City Healthcare System, Northern Territory Health Services, Royal Darwin Hospital
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: Improving blood vessel function in severe malaria, Research & Training to reduce morbidity & mortality from malaria in Papua ( Indonesia)& Papua New Guinea, Decreased nitric oxide, severe malaria, Hyperphenylalaninemia in cerebral malaria, G3342243461, G346870772, G5650507700, G5816694778, G6132571428, Arginine, Nitric Oxide, and Severe Malaria, G6494912503, G675268645, Optimising antimalarial combination therapies in an area coendemic for vivax and falciparum malaria, Tropical Disease - immunity, pathogenesis and vaccine development: global translation, Nitric Oxide and Severe Malaria, Nitric Oxide and Malaria, Hyperphenylalaninemia in cerebral malaria, G893993069, Pathophysiology and treatment of malaria and other tropical infectious diseases prevalent in our region
OpenAlex ID: W2029510081