PMID:22253593

Citation	Stone, EF, Fulton, BO, Ayres, JS, Pham, LN, Ziauddin, J and Shirasu-Hiza, MM (2012) The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. PLoS Pathog. 8:e1002445
Abstract	Survival of bacterial infection is the result of complex host-pathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Previously, we demonstrated that Drosophila mutants lacking the circadian regulatory proteins Timeless (Tim) and Period (Per) are sensitive to infection by S. pneumoniae. Sensitivity to infection can be mediated either by changes in resistance (control of microbial load) or tolerance (endurance of the pathogenic effects of infection). Here we show that Tim regulates resistance against both S. pneumoniae and S. marcescens. We set out to characterize and identify the underlying mechanism of resistance that is circadian-regulated. Using S. pneumoniae, we found that resistance oscillates daily in adult wild-type flies and that these oscillations are absent in Tim mutants. Drosophila have at least three main resistance mechanisms to kill high levels of bacteria in their hemolymph: melanization, antimicrobial peptides, and phagocytosis. We found that melanization is not circadian-regulated. We further found that basal levels of AMP gene expression exhibit time-of-day oscillations but that these are Tim-independent; moreover, infection-induced AMP gene expression is not circadian-regulated. We then show that phagocytosis is circadian-regulated. Wild-type flies exhibit up-regulated phagocytic activity at night; Tim mutants have normal phagocytic activity during the day but lack this night-time peak. Tim appears to regulate an upstream event in phagocytosis, such as bacterial recognition or activation of phagocytic hemocytes. Interestingly, inhibition of phagocytosis in wild type flies results in survival kinetics similar to Tim mutants after infection with S. pneumoniae. Taken together, these results suggest that loss of circadian oscillation of a specific immune function (phagocytosis) can have significant effects on long-term survival of infection.
Links	PubMed PMC3257305 Online version:10.1371/journal.ppat.1002445
Keywords	Animals; Animals, Genetically Modified; Bacteria/growth & development; Bacteria/immunology; Bacteria/metabolism; Bacterial Infections/genetics; Bacterial Infections/microbiology; Bacterial Infections/mortality; Base Sequence; Circadian Rhythm Signaling Peptides and Proteins/genetics; Circadian Rhythm Signaling Peptides and Proteins/physiology; Colony Count, Microbial; Drosophila/genetics; Drosophila/immunology; Drosophila/microbiology; Drosophila Proteins/genetics; Drosophila Proteins/physiology; Host-Pathogen Interactions; Male; Models, Biological; Molecular Sequence Data; Phagocytosis/genetics; Survival Analysis
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
DROME:TIM	involved_in	GO:0050766: positive regulation of phagocytosis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
DROME:TIM	involved_in	GO:0050764: regulation of phagocytosis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
DROME:TIM		GO:0050764: regulation of phagocytosis	ECO:0000315:		P		Figure 5: Tim mutant flies do not express increased phagocytosis during circadian cycles when exposed to S. aureus	complete CACAO 6721
DROME:TIM		GO:0050766: positive regulation of phagocytosis	ECO:0000315:		P		Figure 5: Tim mutant flies do not express increased phagocytosis during circadian cycles when exposed to S. aureus	complete CACAO 7035

References

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