Editors' ChoiceCircadian Biology

A bad time of day to get an infection

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Sci. Signal.  24 May 2016:
Vol. 9, Issue 429, pp. ec120
DOI: 10.1126/scisignal.aag1854

Immune function varies in a circadian pattern. Gagnidze et al. found that this circadian pattern affected the mortality of mice intranasally infected with vesicular stomatitis virus (VSV), which enters the sensory neurons in the nose, travels to the olfactory bulb, and then infects the brain, causing encephalitis. Most of the mice (95%) infected at the start of the rest period of the cycle (light for mice, ZT0) died, whereas less than half (40%) of those infected at the start of the active period (dark, ZT12) died. Mice infected at both time points exhibited an antiviral and proinflammatory cytokine response, but the pattern of accumulation in the blood differed. ZT0-infected animals had a persistent proinflammatory response with increased concentrations of the proinflammatory cytokine CCL2 and also had sustained accumulation of the anti-inflammatory hormone cortisone. Compared with the olfactory bulb of ZT12-infected mice, the ZT0-infected mice also exhibited increased accumulation of monocytes, macrophages, and effector dendritic cells, which was associated with increased proinflammatory cytokine transcripts. Of the transcripts encoding transcription factors that regulate the circadian cycle, the mRNA for the circadian regulatory transcription factor Rev-ERBα was highest at ZT12 in the olfactory bulb of uninfected mice. Pharmacological inhibition of Rev-ERBα increased the mortality of the ZT12-infected mice, which was associated with an increase in Ccl2 transcripts in the olfactory bulb 12 hours after infection (consistent with the time when Rev-ERBα protein would be present). The authors propose that Rev-ERBα may suppress Ccl2 expression to limit the infiltration of proinflammatory monocytes that cause the excessive neuroinflammation resulting in death. These data show that time of infection is a critical factor in the immune response, which can have profound effects on the outcome of the infection.

K. Gagnidze, K. H. Hajdarovic, M. Moskalenko, I. N. Karatsoreos, B. S. McEwen, K. Bulloch, Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis. Proc. Natl. Acad. Sci. U.S.A. 113, 5730–5735 (2016). [PubMed]