Glucose metabolism mediates disease tolerance in cerebral malaria

Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11042-11047. doi: 10.1073/pnas.1806376115. Epub 2018 Oct 5.


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 corresponding metabolic programs to actuate tissue-protective 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 vehicle-treated 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 2DG-treated 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.

Keywords: inflammation; malaria; metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / immunology
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / parasitology
  • Brain / immunology*
  • Brain / parasitology*
  • Disease Models, Animal
  • Glucose / immunology*
  • Glucose / metabolism*
  • Immune Tolerance / immunology*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / parasitology
  • Malaria, Cerebral / immunology*
  • Malaria, Cerebral / metabolism*
  • Malaria, Cerebral / parasitology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Parasitemia / immunology
  • Plasmodium berghei / immunology


  • Glucose