Neonatal oxygen increases sensitivity to influenza A virus infection in adult mice by suppressing epithelial expression of Ear1

Am J Pathol. 2012 Aug;181(2):441-51. doi: 10.1016/j.ajpath.2012.05.005. Epub 2012 Jun 5.


Oxygen exposure in premature infants is a major risk factor for bronchopulmonary dysplasia and can impair the host response to respiratory viral infections later in life. Similarly, adult mice exposed to hyperoxia as neonates display alveolar simplification associated with a reduced number of alveolar epithelial type II cells and exhibit persistent inflammation, fibrosis, and mortality when infected with influenza A virus. Because type II cells participate in innate immunity and alveolar repair, their loss may contribute to oxygen-mediated sensitivity to viral infection. A genomewide screening of type II cells identified eosinophil-associated RNase 1 (Ear1). Ear1 was also detected in airway epithelium and was reduced in lungs of mice exposed to neonatal hyperoxia. Electroporation-mediated gene delivery of Ear1 to the lung before infection successfully reduced viral replication and leukocyte recruitment during infection. It also diminished the enhanced morbidity and mortality attributed to neonatal hyperoxia. These findings demonstrate that novel epithelial expression of Ear1 functions to limit influenza A virus infection, and its loss contributes to oxygen-associated epithelial injury and fibrosis after infection. People born prematurely may have defects in epithelial innate immunity that increase their risk for respiratory viral infections.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Air
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Animals, Newborn
  • Electroporation
  • Eosinophil-Derived Neurotoxin / metabolism*
  • Epithelium / drug effects
  • Epithelium / metabolism*
  • Epithelium / pathology
  • Epithelium / virology
  • Female
  • Gene Transfer Techniques
  • Hyperoxia / complications
  • Hyperoxia / pathology
  • Hyperoxia / virology
  • Influenza A virus / drug effects
  • Influenza A virus / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Orthomyxoviridae Infections / metabolism*
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / prevention & control
  • Orthomyxoviridae Infections / virology*
  • Oxygen / pharmacology*
  • Ribonucleases / metabolism*


  • Ear1 protein, mouse
  • Eosinophil-Derived Neurotoxin
  • Ribonucleases
  • Oxygen