title: Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria.
abstract: 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.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville.|Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Alkaitis
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Honghui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville.
authors.forename: Allison K
authors.initials: AK
authors.lastname: Ikeda
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Rowley
authors.affiliation: Department of Eye and Vision Science, University of Liverpool.|Centre for Clinical Brain Sciences, University of Edinburgh.|Malawi-Liverpool-Wellcome Trust Clinical Research Programme.
authors.forename: Ian J C
authors.initials: IJ
authors.lastname: MacCormick
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Chertow
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton.
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Suffredini
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington.|National Health Service Blood and Transplant, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Roberts
authors.affiliation: Michigan State University, East Lansing.|Blantyre Malaria Project, Malawi.
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.affiliation: Michigan State University, East Lansing.|Blantyre Malaria Project, Malawi.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Seydel
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Ackerman
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics; D001120:Arginine / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D002956:Citrulline / Q000097:blood; D005260:Female; D006801:Humans; D007223:Infant; D008288:Malaria / Q000473:pathology*; D016779:Malaria, Cerebral / Q000473:pathology*; D008295:Malawi; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009952:Ornithine / Q000097:blood; D010949:Plasma / Q000737:chemistry*; D010962:Plasmodium berghei / Q000254:growth & development*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D002956:Citrulline; D001120:Arginine; D009952:Ornithine; D001119:Arginase
keywords: endothelium; host response; metabolism; nitric oxide; plasmodium; urea cycle