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

Pedro Mejia, J. Humberto Treviño-Villarreal, Christopher Hine, Eylul Harputlugil, Samantha Lang, Ediz Calay, Rick Rogers, Dyann Wirth, Manoj T. Duraisingh and James R. Mitchell ()
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Pedro Mejia: Harvard School of Public Health
J. Humberto Treviño-Villarreal: Harvard School of Public Health
Christopher Hine: Harvard School of Public Health
Eylul Harputlugil: Harvard School of Public Health
Samantha Lang: Harvard School of Public Health
Ediz Calay: Harvard School of Public Health
Rick Rogers: Harvard School of Public Health
Dyann Wirth: Harvard School of Public Health
Manoj T. Duraisingh: Harvard School of Public Health
James R. Mitchell: Harvard School of Public Health

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7050

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