title: Targeting glutamine metabolism rescues mice from late-stage cerebral malaria.
abstract: The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15-25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-L-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood-brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8(+) effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood-brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8(+) T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Emile B
authors.initials: EB
authors.lastname: Gordon
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Hart
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Tuan M
authors.initials: TM
authors.lastname: Tran
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Michael
authors.initials: M
authors.lastname: Waisberg
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Munir
authors.initials: M
authors.lastname: Akkaya
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Ann S
authors.initials: AS
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55454;
authors.forename: Sara E
authors.initials: SE
authors.lastname: Hamilton
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Mirna
authors.initials: M
authors.lastname: Pena
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Takele
authors.initials: T
authors.lastname: Yazew
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
authors.forename: Chen-Feng
authors.initials: CF
authors.lastname: Qi
authors.affiliation: Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287; Chang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Taoyuan 333, Taiwan;
authors.forename: Chen-Fang
authors.initials: CF
authors.lastname: Lee
authors.affiliation: Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Lo
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852 lmiller@niaid.nih.gov Jpowell@jhmi.edu spierce@nih.gov.
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
authors.affiliation: Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287; lmiller@niaid.nih.gov Jpowell@jhmi.edu spierce@nih.gov.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; lmiller@niaid.nih.gov Jpowell@jhmi.edu spierce@nih.gov.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects; D003980:Diazooxonorleucine / Q000494:pharmacology / Q000627:therapeutic use*; D005973:Glutamine / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000188:drug therapy* / Q000378:metabolism; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice
chemical_list: D000962:Antimalarials; D003980:Diazooxonorleucine; D005973:Glutamine
keywords: CD8+ T cells; DON; adjunctive therapy; cerebral malaria; glutamine metabolism