Biological Rhythms in Coronavirus Pneumonia Pathogenesis.

Night shift work is linked to more severe coronavirus pneumonia, suggesting that host resilience to these pathogens may depend on the timing of exposure. Here, we examined how the time of day influences the severity of coronavirus pneumonia in mice, using mouse hepatitis virus-1 (MHV-1) as a natural infection model. We found that the timing of infection influenced MHV-1 severity, with the highest mortality, peak viral load, and lung inflammation occurring with midday infection, which corresponds to the mid-rest phase in mice and is comparable with nighttime in humans. The time-of-day dependence in disease severity occurred prominently in males and was sensitive to global disruption of the clock gene Bmal1. Midday infection correlated with increased MHV-1 binding to and replication within alveolar macrophages (AM). Depleting AMs with clodronate or loading them with neutral liposomes before MHV-1 infection eliminated differences in pneumonia survival and peak viral load related to the timing of infection. These data suggest an immunologic rhythm underlying coronavirus outcomes, in which oscillations in "first contact" interactions between AMs and the virus shape subsequent pneumonia severity.