The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila

PLoS Pathogens

Ben O. Fulton¹  Junaid Ziauddin²  Linh N. Pham²  Janelle S. Ayres²  Mimi M. Shirasu-Hiza²  Elizabeth F. Stone³ 

[1] Department of Genetics and Development, Columbia University Medical School, New York, New York, United States of America;Department of Microbiology and Immunology, Stanford University Medical School, Stanford, California, United States of America;Department of Neurobiology and Behavior, Columbia University Medical School, New York, New York, United States of America

关键词: Phagocytosis;    Pneumococcus;    Circadian oscillators;    Circadian rhythms;    Bacterial pathogens;    Chronobiology;    Gene expression;    Staphylococcus aureus;   

DOI  :  10.1371/journal.ppat.1002445

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY