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.
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