title: Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression.
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.
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Pedro
authors: P
authors: Mejia
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.|Department of Environmental Health, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: J Humberto
authors: JH
authors: Treviño-Villarreal
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Christopher
authors: C
authors: Hine
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Eylul
authors: E
authors: Harputlugil
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Samantha
authors: S
authors: Lang
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Ediz
authors: E
authors: Calay
authors: Department of Environmental Health, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Rick
authors: R
authors: Rogers
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Dyann
authors: D
authors: Wirth
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: Manoj T
authors: MT
authors: Duraisingh
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115 USA.
authors: James R
authors: JR
authors: Mitchell
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D031204:Caloric Restriction; D005260:Female; D020738:Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000517:prevention & control*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020738:Leptin; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
references: Parasitology. 2010 Apr;137(5):755-72
references: 20028608
references: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11468-73
references: 16051702
references: Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E322-30
references: 12388166
references: J Immunol. 2007 May 1;178(9):5779-88
references: 17442962
references: Curr Immunol Rev. 2008 May 1;4(2):70-79
references: 20198122
references: Ann Trop Paediatr. 1981 Jun;1(2):87-91
references: 6185057
references: J Immunol. 2010 Sep 15;185(6):3632-42
references: 20720206
references: J Biol Chem. 2011 Feb 11;286(6):4429-42
references: 21119198
references: Science. 2005 Nov 18;310(5751):1193-6
references: 16293764
references: Cell. 2010 Feb 5;140(3):338-48
references: 20144759
references: Cell Rep. 2014 Aug 21;8(4):1160-70
references: 25131199
references: Aging Cell. 2014 Jun;13(3):468-77
references: 24341993
references: Infect Immun. 2010 Sep;78(9):4033-9
references: 20605973
references: Parasitology. 1993 Dec;107 ( Pt 5):471-6
references: 8295786
references: Annu Rev Immunol. 2012;30:39-68
references: 22136167
references: PLoS Pathog. 2009 Apr;5(4):e1000369
references: 19343215
references: Nat Rev Immunol. 2006 Oct;6(10):772-83
references: 16998510
references: Exp Gerontol. 2009 Jan-Feb;44(1-2):41-5
references: 18502597
references: Cell Mol Immunol. 2007 Feb;4(1):1-13
references: 17349207
references: Trends Parasitol. 2012 Apr;28(4):151-60
references: 22365903
references: Curr Biol. 2007 Oct 9;17(19):1646-56
references: 17900900
references: Nat Immunol. 2008 May;9(5):513-21
references: 18391955
references: Exp Gerontol. 2013 Oct;48(10):1043-8
references: 23376627
references: Folia Parasitol (Praha). 2002;49(4):249-51
references: 12641196
references: Nature. 2009 Jul 16;460(7253):392-5
references: 19587680
references: Acta Trop. 1992 Apr;50(4):285-93
references: 1356299
references: Science. 2009 Oct 2;326(5949):140-4
references: 19797661
references: Am J Physiol Endocrinol Metab. 2010 Jan;298(1):E108-16
references: 19887594
references: Cell Cycle. 2008 Jun 15;7(12):1713-7
references: 18583936
references: J Immunol. 2012 Sep 15;189(6):2941-53
references: 22904304
references: J Immunol. 2010 Aug 15;185(4):2004-8
references: 20631309
references: J Immunol. 2006 Jun 15;176(12):7745-52
references: 16751422
references: J Immunol. 2008 Jan 15;180(2):1217-30
references: 18178862
references: J Immunol. 2008 Jul 15;181(2):1420-8
references: 18606696
references: Parasite Immunol. 2008 Oct;30(10):544-53
references: 18665903
references: J Infect Dis. 2000 Sep;182 Suppl 1:S37-53
references: 10944483
references: Int J Parasitol. 2011 Feb;41(2):155-63
references: 20828575
references: Eur J Immunol. 2008 Apr;38(4):1082-95
references: 18383042
references: Mol Aspects Med. 2011 Jun;32(3):159-221
references: 21840335
references: Nat Rev Immunol. 2011 Feb;11(2):81
references: 21469396
references: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4814-9
references: 18347328
references: PLoS One. 2011;6(4):e18720
references: 21494565
references: Malar J. 2008;7:81
references: 18489748
references: Cytometry A. 2009 Mar;75(3):225-35
references: 18785271
references: Lancet. 2010 Nov 6;376(9752):1517-21
references: 21035844
references: Nat Rev Immunol. 2011 Feb;11(2):109-17
references: 21233853