Biological Rhythms in Coronavirus Pneumonia Pathogenesis

Area of Science:

• Immunology
• Chronobiology
• Virology

Background:

• Night shift work is associated with increased severity of coronavirus pneumonia.
• Host resilience to pathogens may depend on the timing of exposure.
• Circadian rhythms influence various physiological processes, including immune responses.

Purpose of the Study:

• To investigate the influence of the time of day on the severity of coronavirus pneumonia in a mouse model.
• To identify the specific immune cells and mechanisms involved in time-dependent disease outcomes.

Main Methods:

• Used mouse hepatitis virus-1 (MHV-1) as a natural infection model in mice.
• Infected mice at different times of day to assess disease severity, viral load, and lung inflammation.
• Examined the role of the clock gene Bmal1 and alveolar macrophages (AMs) in time-dependent disease severity.
• Depleted AMs using clodronate or liposomes to evaluate their contribution.

Main Results:

• The timing of MHV-1 infection significantly influenced pneumonia severity, with midday infections (mid-rest phase) showing the highest mortality, viral load, and inflammation.
• Time-of-day effects were more pronounced in male mice and were dependent on the clock gene Bmal1.
• Midday infection led to increased MHV-1 binding and replication in alveolar macrophages.
• Depletion or manipulation of AMs before infection abolished the time-of-day differences in survival and viral load.

Conclusions:

• An immunologic rhythm underlies coronavirus pneumonia outcomes.
• Oscillations in the interaction between alveolar macrophages and the virus at the time of initial exposure shape subsequent disease severity.
• Targeting circadian-regulated immune cell functions could offer new therapeutic strategies for viral respiratory infections.