Loss of circadian protection against influenza infection in adult mice exposed to hyperoxia as neonates

Adverse early-life exposures have a lasting negative impact on health. Neonatal hyperoxia that is a risk factor for bronchopulmonary dysplasia confers susceptibility to influenza A virus (IAV) infection later in life. Given our previous findings that the circadian clock protects against IAV, we asked if the long-term impact of neonatal hyperoxia vis-a-vis IAV infection includes circadian disruption. Here, we show that neonatal hyperoxia abolishes the clock-mediated time of day protection from IAV in mice, independent of viral burden through host tolerance pathways. We discovered that the lung intrinsic clock (and not the central or immune clocks) mediated this dysregulation. Loss of circadian protein, Bmal1, in alveolar type 2 (AT2) cells recapitulates the increased mortality, loss of temporal gating, and other key features of hyperoxia-exposed animals. Our data suggest a novel role for the circadian clock in AT2 cells in mediating long-term effects of early-life exposures to the lungs.

Automated summary

Early-life exposure to neonatal hyperoxia eliminates the clock-mediated protection against influenza A virus infection in mice, mainly through dysregulation of the lung intrinsic clock. Loss of the circadian protein Bmal1 in AT2 cells recapitulates the increased mortality and loss of temporal gating observed in animals exposed to hyperoxia. These findings suggest a novel role for the circadian clock in AT2 cells in mediating the long-term effects of early-life exposures to the lungs.