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: Emile B Gordon, Geoffrey T Hart, Tuan M 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 42 Pg. 13075-80 (Oct 20 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26438846 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antimalarials
• Diazooxonorleucine
• Glutamine

Topics

• Animals
• Antimalarials (pharmacology, therapeutic use)
• Blood-Brain Barrier (drug effects)
• Diazooxonorleucine (pharmacology, therapeutic use)
• Glutamine (metabolism)
• Malaria, Cerebral (drug therapy, metabolism)
• Malaria, Falciparum (drug therapy, metabolism)
• Mice