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Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

  1. Susan K. Piercea,5
  1. aLaboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852;
  2. bDepartment of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55454;
  3. cSidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
  4. dChang-Gung Transplantation Institute, Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Taoyuan 333, Taiwan;
  5. eLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

  1. Contributed by Louis H. Miller, August 26, 2015 (sent for review June 19, 2015; reviewed by James R. Mitchell)

Significance

Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection in African children despite effective antimalarial treatment. Once signs of neurologic disease have commenced, there is no adjunctive treatment for CM, and overall mortality remains high. Thus, a treatment that arrests disease and promotes healing in the late stages is urgently needed. Here we report, in an animal model of CM, that the glutamine analog 6-diazo-5-oxo-L-norleucine (DON) is an effective therapy even when treatment is initiated after infected animals show neurological signs of disease. Within hours of DON treatment blood–brain barrier integrity was restored, and brain swelling was reduced. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children.

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.

Footnotes

  • ↵1E.B.G., G.T.H., and T.M.T. contributed equally to this work.

  • ↵2Present address: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

  • ↵3Present address: Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, IN 46202.

  • ↵4Present address: Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22903.

  • ↵5To whom correspondence may be addressed. Email: lmiller{at}niaid.nih.gov, Jpowell{at}jhmi.edu, or spierce{at}nih.gov.

  • Author contributions: E.B.G., G.T.H., T.M.T., M.W., L.H.M., J.D.P., and S.K.P. designed research; E.B.G., G.T.H., T.M.T., M.W., M.A., A.S.K., S.E.H., M.P., T.Y., C.-F.Q., C.-F.L., and Y.-C.L. performed research; E.B.G., G.T.H., T.M.T., M.W., M.A., A.S.K., C.-F.Q., C.-F.L., Y.-C.L., and J.D.P. analyzed data; and E.B.G., G.T.H., T.M.T., L.H.M., J.D.P., and S.K.P. wrote the paper.

  • Reviewers included: J.R.M., Harvard School of Public Health.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516544112/-/DCSupplemental.

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