title: period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection.
abstract: Most metazoans undergo dynamic, circadian-regulated changes in behavior and physiology. Currently, it is unknown how circadian-regulated behavior impacts immunity against infection. Two broad categories of defense against bacterial infection are resistance, control of microbial growth, and tolerance, control of the pathogenic effects of infection. Our study of behaviorally arrhythmic Drosophila circadian period mutants identified a novel link between nutrient intake and tolerance of infection with B. cepacia, a bacterial pathogen of rising importance in hospital-acquired infections. We found that infection tolerance in wild-type animals is stimulated by acute exposure to dietary glucose and amino acids. Glucose-stimulated tolerance was induced by feeding or direct injection; injections revealed a narrow window for glucose-stimulated tolerance. In contrast, amino acids stimulated tolerance only when ingested. We investigated the role of a known amino-acid-sensing pathway, the TOR (Target of Rapamycin) pathway, in immunity. TORC1 is circadian regulated and inhibition of TORC1 decreased resistance, as in vertebrates. Surprisingly, inhibition of the less well-characterized TOR complex 2 (TORC2) dramatically increased survival, through both resistance and tolerance mechanisms. This work suggests that dietary intake on the day of infection by B. cepacia can make a significant difference in long-term survival. We further demonstrate that TOR signaling mediates both resistance and tolerance of infection and identify TORC2 as a novel potential therapeutic target for increasing survival of infection.
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Victoria W
authors.initials: VW
authors.lastname: Allen
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Reed M
authors.initials: RM
authors.lastname: O'Connor
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ulgherait
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Clarice G
authors.initials: CG
authors.lastname: Zhou
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Stone
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hill
authors.affiliation: Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Murphy
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Canman
authors.affiliation: Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Ja
authors.affiliation: Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: ms4095@cumc.columbia.edu.
authors.forename: Mimi M
authors.initials: MM
authors.lastname: Shirasu-Hiza
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000596:Amino Acids; D029721:Drosophila Proteins; D046912:Multiprotein Complexes; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Burkholderia cepacia; Drosophila; Rictor; TOR; TORC1; TORC2; amino acids; circadian; diet; feeding; glucose; immunity; infection; period mutant; resistance; tolerance