Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation

PLoS Pathogens

Donald L. Granger¹  Nicholas M. Anstey²  Tsin W. Yeo³  Keith Hyland³  Enny Kenangalem⁴  Daniel A. Lampah⁵  Ric N. Price⁶  Emiliana Tjitra⁶  J. Brice Weinberg⁷ 

[1]Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom

[2]Duke University and VA Medical Centers, Durham, North Carolina, United States of America

[3]Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia

[4]Institute of Infectious Disease and Epidemiology, Tan Tock Seng Hospital, Singapore

[5]Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

[6]Menzies School of Health Research-National Institute of Health Research and Development Research Program, and District Ministry of Health, Timika, Papua, Indonesia

[7]National Institute of Health Research and Development, Jakarta, Indonesia

关键词: Malaria;    Nitric oxide;    Phenylalanine;    Creatinine;    Metabolites;    Urine;    Malarial parasites;    Severe sepsis;   

DOI  :  10.1371/journal.ppat.1004667

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY