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.
Highlights
Survival of bacterial infection is the result of complex hostpathogen interactions
Though immune parameters are known to vary with time of day, circadian regulation of the immune system is not well understood
We found that only the phagocytic activity of host immune cells is circadian-regulated and peaks at night, during the rest phase
Summary
Survival of bacterial infection is the result of complex hostpathogen interactions. An often-overlooked aspect of these interactions is the circadian state of the host. Microarray analyses of different vertebrate tissues, such as heart, liver, or spleen-derived macrophages, have shown that approximately 5–10% of total gene expression in each tissue is circadian-regulated [2,3] These oscillations in transcription are thought to underlie circadian changes in the organism’s physiology and behavior. Reflecting the pervasiveness of circadian regulation, the Drosophila circadian mutants Timeless (Tim) and Period (Per) have pleiotropic phenotypes They exhibit loss of circadian rhythms in locomotor activity, eclosion, male courtship, and oxidative stress response [4,5,6]. These circadian mutants are sensitive to infection by at least two bacterial pathogens and resistant to infection by another [7,8]. Microarray analysis comparing wild type and circadian mutants suggested that expression of immune signaling molecules that induce resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
