Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Emile B. Gordon, Geoffrey T. Hart, Tuan  Tran, Michael Waisberg, Munir Akkaya, Ann S. Kim, Sara E. Hamilton, Mirna Pena, Takele Yazew, Chen Feng Qi, Chen Fang Lee, Ying Chun Lo, Louis H. Miller, Jonathan D. Powell, Susan K. Pierce

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13075-13080
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number42
DOIs
StatePublished - Oct 20 2015

Fingerprint

Cerebral Malaria
Diazooxonorleucine
Glutamine
Brain Edema
Blood-Brain Barrier
Brain
T-Lymphocytes
Antimalarials
Therapeutics
Plasmodium falciparum
Malaria
Parasites
Erythrocytes
Drug Therapy
Mortality
Infection

Keywords

  • Adjunctive therapy
  • CD8 T cells
  • Cerebral malaria
  • DON
  • Glutamine metabolism

ASJC Scopus subject areas

  • General

Cite this

Targeting glutamine metabolism rescues mice from late-stage cerebral malaria. / Gordon, Emile B.; Hart, Geoffrey T.; Tran, Tuan ; Waisberg, Michael; Akkaya, Munir; Kim, Ann S.; Hamilton, Sara E.; Pena, Mirna; Yazew, Takele; Qi, Chen Feng; Lee, Chen Fang; Lo, Ying Chun; Miller, Louis H.; Powell, Jonathan D.; Pierce, Susan K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 42, 20.10.2015, p. 13075-13080.

Research output: Contribution to journalArticle

Gordon, EB, Hart, GT, Tran, T, Waisberg, M, Akkaya, M, Kim, AS, Hamilton, SE, Pena, M, Yazew, T, Qi, CF, Lee, CF, Lo, YC, Miller, LH, Powell, JD & Pierce, SK 2015, 'Targeting glutamine metabolism rescues mice from late-stage cerebral malaria', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 42, pp. 13075-13080. https://doi.org/10.1073/pnas.1516544112
Gordon, Emile B. ; Hart, Geoffrey T. ; Tran, Tuan  ; Waisberg, Michael ; Akkaya, Munir ; Kim, Ann S. ; Hamilton, Sara E. ; Pena, Mirna ; Yazew, Takele ; Qi, Chen Feng ; Lee, Chen Fang ; Lo, Ying Chun ; Miller, Louis H. ; Powell, Jonathan D. ; Pierce, Susan K. / Targeting glutamine metabolism rescues mice from late-stage cerebral malaria. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 42. pp. 13075-13080.
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