Glucose metabolism mediates disease tolerance in cerebral malaria

Andrew Wang, Sarah Huen, Harding H. Luan, Kelly Baker, Henry Rinder, Carmen J. Booth, Ruslan Medzhitov

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Sickness behaviors are a conserved set of stereotypic responses to inflammatory diseases. We recently demonstrated that interfering with inflammation-induced anorexia led to metabolic changes that had profound effects on survival of acute inflammatory conditions. We found that different inflammatory states needed to be coordinated with correspondingmetabolic programs to actuate tissueprotective mechanisms. Survival of viral inflammation required intact glucose utilization pathways, whereas survival of bacterial inflammation required alternative fuel substrates and ketogenic programs. We thus hypothesized that organismal metabolism would be important in other classes of infectious inflammation and sought to understand its role in the prototypic parasitic disease malaria. Utilizing the cerebral malaria model, Plasmodium berghei ANKA (PbA) infection in C57BL/6J male mice, we unexpectedly found that inhibition of glycolysis using 2-deoxy glucose (2DG) conferred protection from cerebral malaria. Unlike vehicletreated animals, 2DG-treated animals did not develop cerebral malaria and survived until ultimately succumbing to fatal anemia. We did not find any differences in parasitemia or pathogen load in affected tissues. There were no differences in the kinetics of anemia. We also did not detect differences in immune infiltration in the brain or in blood-brain barrier permeability. Rather, on pathological analyses performed on the entire brain, we found that 2DG prevented the formation of thrombi and thrombotic complications. Using thromboelastography (TEG), we found that 2DGtreated animals formed clots that were significantly less strong and stable. Together, these data suggest that glucose metabolism is involved in inflammation-induced hemostasis and provide a potential therapeutic target in treatment of cerebral malaria.

Original languageEnglish (US)
Pages (from-to)11042-11047
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number43
DOIs
StatePublished - Oct 23 2018

Fingerprint

Cerebral Malaria
Inflammation
Glucose
Anemia
Thrombelastography
Illness Behavior
Plasmodium berghei
Parasitic Diseases
Parasitemia
Brain
Anorexia
Glycolysis
Hemostasis
Blood-Brain Barrier
Malaria
Permeability
Thrombosis
Infection

Keywords

  • Inflammation
  • Malaria
  • Metabolism

ASJC Scopus subject areas

  • General

Cite this

Glucose metabolism mediates disease tolerance in cerebral malaria. / Wang, Andrew; Huen, Sarah; Luan, Harding H.; Baker, Kelly; Rinder, Henry; Booth, Carmen J.; Medzhitov, Ruslan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 43, 23.10.2018, p. 11042-11047.

Research output: Contribution to journalArticle

Wang, Andrew ; Huen, Sarah ; Luan, Harding H. ; Baker, Kelly ; Rinder, Henry ; Booth, Carmen J. ; Medzhitov, Ruslan. / Glucose metabolism mediates disease tolerance in cerebral malaria. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 43. pp. 11042-11047.
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