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

Pedro Mejia,Dyann Wirth,Manoj T Duraisingh,Rick Rogers,J Humberto Treviño-Villarreal,James R Mitchell,Samantha Lang,Ediz Calay,Eylul Harputlugil,Christopher Hine

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 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 signaling 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.

Highlights

Host nutrition can affect the outcome of parasitic diseases through metabolic effects on host immunity and/or the parasite
Mice were subject to varying degrees of Dietary restriction (DR) (10–50%) relative to ad libitum (AL)-fed controls starting 7 days before infection on day 0 with P. berghei ANKA-infected red blood cells (RBCs) (Fig. 1a–e), or restricted at 40% starting at different time points ( À 7, À 4, À 2, 0 or þ 2 days of infection, Fig. 1f–j)
To test Mechanistic target of rapamycin complex 1 (mTORC1) activity in immune cells as the potential link between DR and leptin action in malarial infection, we looked at markers of mTORC1 activity in whole spleens, non-adherent splenocytes enriched for lymphocytes and adherent splenocytes enriched for macrophages and dendritic cells, isolated from AL or DR animals on day 3 after infection

Summary

Introduction

Host nutrition can affect the outcome of parasitic diseases through metabolic effects on host immunity and/or the parasite. Leptin is secreted by white adipocytes in proportion to the percent body fat[8] Leptin acts both centrally and peripherally to reduce appetite and increase energy expenditure, in part through modulation of mTORC1 activity. We report that brief periods of DR starting on the day of infection prevent severe ECM symptoms and death in mice through modulation of leptin levels and mTORC1 activation in CD4 þ and CD8 þ T cells, resulting in increased numbers of active T cells in the spleen and less in the brain late in infection when severe neurological symptoms arise. Pharmacological inhibition of either leptin signalling with a mutant peptide, or downstream mTORC1 signalling with rapamycin, blocks ECM symptoms and reduces mortality, revealing two novel host targets for potential treatment of CM

Methods

Results

Conclusion