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Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria
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2016 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 214, no 12, p. 1840-1849Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:  Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endothelium-dependent vasodilation. Increased conversion of arginine to ornithine by parasites or host arginase is a proposed mechanism of arginine depletion.

METHODS:  We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope-labeled tracers measured by quadrupole time-of-flight liquid chromatography-mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice.

RESULTS:  Children with cerebral malaria and P. berghei-infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice.

CONCLUSIONS:  Simultaneous arginine and ornithine depletion in malaria parasite-infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance.

Place, publisher, year, edition, pages
Oxford University Press, 2016. Vol. 214, no 12, p. 1840-1849
Keywords [en]
metabolism, host response, plasmodium, nitric oxide, endothelium, urea cycle
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-165842DOI: 10.1093/infdis/jiw452ISI: 000393130000011PubMedID: 27923948OAI: oai:DiVA.org:umu-165842DiVA, id: diva2:1379083
Funder
NIH (National Institute of Health), T32GM007753Wellcome trust, WT098051Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2019-12-18Bibliographically approved

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Billker, Oliver

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