The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila

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...

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Main Authors:	Stone, Elizabeth F., Fulton, Ben O., Ayres, Janelle S., Pham, Linh N., Ziauddin, Junaid, Shirasu-Hiza, Mimi M.
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257305/

id	pubmed-3257305
recordtype	oai_dc
spelling	pubmed-32573052012-01-17 The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila Stone, Elizabeth F. Fulton, Ben O. Ayres, Janelle S. Pham, Linh N. Ziauddin, Junaid Shirasu-Hiza, Mimi M. Research Article 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. Public Library of Science 2012-01-12 /pmc/articles/PMC3257305/ /pubmed/22253593 http://dx.doi.org/10.1371/journal.ppat.1002445 Text en Stone et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Stone, Elizabeth F. Fulton, Ben O. Ayres, Janelle S. Pham, Linh N. Ziauddin, Junaid Shirasu-Hiza, Mimi M.
spellingShingle	Stone, Elizabeth F. Fulton, Ben O. Ayres, Janelle S. Pham, Linh N. Ziauddin, Junaid Shirasu-Hiza, Mimi M. The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila
author_facet	Stone, Elizabeth F. Fulton, Ben O. Ayres, Janelle S. Pham, Linh N. Ziauddin, Junaid Shirasu-Hiza, Mimi M.
author_sort	Stone, Elizabeth F.
title	The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila
title_short	The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila
title_full	The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila
title_fullStr	The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila
title_full_unstemmed	The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila
title_sort	circadian clock protein timeless regulates phagocytosis of bacteria in drosophila
description	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.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257305/
_version_	1611499653227872256

The Circadian Clock Protein Timeless Regulates Phagocytosis of Bacteria in Drosophila

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