period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection

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. •Circadian per mutants have increased feeding and increased tolerance of B. cepacia•Both dietary glucose and amino acids contribute to host tolerance of B. cepacia•Loss of Drosophila TORC1 decreases resistance against B. cepacia•In contrast to dTORC1, dTORC2 inhibits both resistance and tolerance Allen et al. use Drosophila circadian period mutants to link acute nutrient intake and increased tolerance of B. cepacia infection. They found that, as in vertebrates, dTORC1 activity is circadian regulated and increases resistance. Unexpectedly, loss of dTORC2 activity increased both resistance and tolerance of infection.