1. Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression.
- Author
-
Mejia P, Treviño-Villarreal JH, Hine C, Harputlugil E, Lang S, Calay E, Rogers R, Wirth D, Duraisingh MT, and Mitchell JR
- Subjects
- Animals, Body Composition drug effects, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes metabolism, Female, Leptin antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Real-Time Polymerase Chain Reaction, Sirolimus pharmacology, Caloric Restriction, Leptin metabolism, Malaria, Cerebral metabolism, Malaria, Cerebral prevention & control, Multiprotein Complexes metabolism, TOR Serine-Threonine Kinases metabolism
- 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.
- Published
- 2015
- Full Text
- View/download PDF