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

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          Abstract

          Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH 4) 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 [BH 4] and the oxidized metabolites, dihydrobiopterin [BH 2] and biopterin [B 0]) 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.

          Author Summary

          Vascular nitric oxide (NO) bioavailability is decreased in severe falciparum malaria and associated with microvascular dysfunction, increased activation of the cells lining blood vessels (endothelial cells) and increased parasite biomass. Tetrahydrobiopterin (BH 4) is an essential cofactor for nitric oxide synthase (NOS) enzymatic conversion of L-arginine to NO and L-citrulline. But when BH 4 is low, NOS is “uncoupled” and produces superoxide instead of NO. In oxidative conditions, BH 4 is oxidized to dihydrobiopterin (BH 2) and biopterin (B 0). BH 2 competes with remaining BH 4 at its NOS binding site, further decreasing NOS-catalyzed NO production. We measured BH 4, BH 2 and B 0 in the urine of children with coma due to falciparum malaria (cerebral malaria), uncomplicated falciparum malaria, children with non-malaria central nervous system conditions and healthy controls. Urine BH 4 was significantly decreased and BH 2 significantly increased in cerebral malaria compared to uncomplicated malaria, non-malaria central nervous conditions and healthy controls, suggesting increased oxidative stress and insufficient recycling of BH 2 back to BH 4. Urine BH 4 concentration was independently associated with increased risk of cerebral malaria. Given that safe therapies for regenerating BH 4 have been studied in chronic vascular disease, this finding of low BH 4 in pediatric cerebral malaria offers a new area of investigation for adjunctive therapies aimed at improving NO bioavailability and, consequently, clinical outcomes in severe falciparum malaria.

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          Most cited references58

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          Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

          The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
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            The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies.

            The angiopoietins Ang-1 and Ang-2 have been identified as ligands with opposing functions of the receptor tyrosine kinase Tie-2 regulating endothelial cell survival and vascular maturation. Ang-1 acts in a paracrine agonistic manner, whereas Ang-2 appears to act primarily as an autocrine antagonistic regulator. To shed further light on the complexity of autocrine/paracrine agonistic/antagonistic functions of the angiopoietin/Tie-2 system, we have studied Ang-2 synthesis and secretion in different populations of wild-type and retrovirally Ang-2-transduced endothelial cells. Endogenous and overexpressed endothelial cell Ang-2 is expressed in a characteristic granular pattern indicative of a cytoplasmic storage granule. Light and electron microscopic double staining revealed Ang-2 colocalization with von Willebrand factor, identifying Ang-2 as a Weibel-Palade body molecule. Costaining with P-selectin showed that storage of Ang-2 and P-selectin in Weibel-Palade bodies is mutually exclusive. Stored Ang-2 has a long half-life of more than 18 hours and can be secreted within minutes of stimulation (eg, by phorbol 12-myristate 13-acetate [PMA], thrombin, and histamine). Collectively, the identification of Ang-2 as a stored, rapidly available molecule in endothelial cells strongly suggests functions of the angiopoietin/Tie-2 system beyond the established roles during angiogenesis likely to be involved in rapid vascular homeostatic reactions such as inflammation and coagulation.
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              Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome.

              Cerebral malaria is the most severe neurological complication of infection with Plasmodium falciparum. With >575,000 cases annually, children in sub-Saharan Africa are the most affected. Surviving patients have an increased risk of neurological and cognitive deficits, behavioral difficulties, and epilepsy making cerebral malaria a leading cause of childhood neurodisability in the region. The pathogenesis of neurocognitive sequelae is poorly understood: coma develops through multiple mechanisms and there may be several mechanisms of brain injury. It is unclear how an intravascular parasite causes such brain injury. Understanding these mechanisms is important to develop appropriate neuroprotective interventions. This article examines possible mechanisms of brain injury in cerebral malaria, relating this to the pathogenesis of the disease, and explores prospects for improved neurocognitive outcome.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                12 March 2015
                March 2015
                : 11
                : 3
                : e1004655
                Affiliations
                [1 ]Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina, United States of America
                [2 ]Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania
                [3 ]Department of Medicine, Intermountain Healthcare, Salt Lake City, Utah, United States of America
                [4 ]Department of Medicine, University of Utah School of Medicine and VA Medical Center, Salt Lake City, Utah, United States of America
                [5 ]Neurochemistry Division, Medical Neurogenetics, Atlanta, Georgia, United States of America
                [6 ]Global and Tropical Health Division, Menzies School for Health Research and Charles Darwin University, Darwin, Australia
                [7 ]Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia
                [8 ]Department of Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
                Albert Einstein College of Medicine, UNITED STATES
                Author notes

                KH is Vice President at Medical Neurogenetics, LLC, Atlanta, GA, a commercial company that performs clinical analyses of pterin metabolites. The pterin assays used in our study are for research purposes only, and are not available from his company commercially. His collaboration in this present work as a clinical chemist has been for research purposes only. KH and Medical Neurogenetics, LLC have not acquired nor do they anticipate to acquire any financial gain as part of this research collaboration. His association with Medical Neurogenetics does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.

                Conceived and designed the experiments: MPR BKL NMA JBW EDM DLG. Performed the experiments: MPR JM SF BKL KH ADV EDM DLG. Analyzed the data: MPR JM SF BKL KH ADV TWY NMA JBW EDM DLG. Wrote the paper: MPR JM SF BKL KH ADV TWY NMA JBW EDM DLG.

                Article
                PPATHOGENS-D-14-01524
                10.1371/journal.ppat.1004655
                4357384
                25764173
                fc553d66-3295-4831-ab65-6ac480aec607

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication

                History
                : 30 June 2014
                : 5 January 2015
                Page count
                Figures: 4, Tables: 4, Pages: 22
                Funding
                The work was supported by the following agencies and grants: National Institutes of Health (U01AI057565 and R01AI041764 [DLG and JBW]); Fogarty International Center Global Health Fellowship (R25TW009343 [MPR]); the Veterans Affairs Research Service (JBW and DLG); and Australian NHMRC Fellowships (NMA and TWY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and Supporting Information.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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