Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression

Nat Commun. 2015 Jan 30;6:6050. doi: 10.1038/ncomms7050.

Abstract

Host nutrition can affect the outcome of parasitic diseases through metabolic effects on host immunity and/or the parasite. Here we show that modulation of mouse immunometabolism through brief restriction of food intake (dietary restriction, DR) prevents neuropathology in experimental cerebral malaria (ECM). While no effects are detected on parasite growth, DR reduces parasite accumulation in peripheral tissues including the brain, and increases clearance in the spleen. Leptin, a host-derived adipokine linking appetite, energy balance and immune function, is required for ECM pathology and its levels are reduced upon DR. Recombinant leptin abrogates DR benefits, while pharmacological or genetic inhibition of leptin signalling protects against ECM. DR reduces mTORC1 activity in T cells, and this effect is abrogated upon leptin administration. Furthermore, mTORC1 inhibition with rapamycin prevents ECM pathology. Our results suggest that leptin and mTORC1 provide a novel mechanistic link between nutrition, immunometabolism and ECM pathology, with potential therapeutic implications for cerebral malaria.

Publication types

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

MeSH terms

  • Animals
  • Body Composition / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Caloric Restriction*
  • Female
  • Leptin / antagonists & inhibitors
  • Leptin / metabolism*
  • Malaria, Cerebral / metabolism*
  • Malaria, Cerebral / prevention & control*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Leptin
  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus