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

Yasmine Issah,Soon Y Tang,Shaon Sengupta,Kaitlyn Forrest,Katherine N Theken,Mara Mermigos,Amita Sehgal,George S Worthen,Thomas G Brooks,Amruta Naik,Nicholas Lahens,Garret A Fitzgerald

doi:10.7554/elife.61241

Abstract

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-à-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.

Highlights

Hyperoxia represents the single most important toxic exposure to premature neonatal lungs and is the key risk factor for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) (Jobe and Bancalari, 2001; Peek et al, 2017)
We report that disrupting Bmal1 in alveolar type 2 (AT2) cells of the lung faithfully recapitulates the phenotype of animals exposed to neonatal hyperoxia, suggesting that early-life hyperoxia disrupts the circadian regulation of the pulmonary response to hyperoxia through the AT2 clock
We hypothesized that neonatal hyperoxia would disrupt circadian rhythms to result in a loss of temporal difference in outcomes in recovered adult mice infected with influenza A virus (IAV) at ZT11(dusk) or ZT23

Summary

Introduction

Hyperoxia represents the single most important toxic exposure to premature neonatal lungs and is the key risk factor for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) (Jobe and Bancalari, 2001; Peek et al, 2017). BPD is associated with an increased risk of respiratory infections, such as asthma (Gough et al, 2014; Yang et al, 2020) and chronic obstructive pulmonary disease (COPD) (Islam et al, 2015; McGrath-Morrow and Collaco, 2019; Savran and Ulrik, 2018). As an increasing number of prematurely born neonates survive into adulthood, these long-term morbidities have acquired greater public health importance (Jain, 2015).

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