Severity of neonatal influenza infection is driven by type I interferon and oxidative stress

Ogan K. Kumova, Ioanna Evdokia Galani, Abhishek Rao, Hannah Johnson, Vasiliki Triantafyllia, Stephanie M. Matt, Judy Pascasio, Peter J. Gaskill, Evangelos Andreakos, Peter D. Katsikis, Alison J. Carey*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNβ 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNβ induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.

Original languageEnglish
Pages (from-to)1309-1320
Number of pages12
JournalMucosal Immunology
Issue number6
Publication statusPublished - Jun 2022

Bibliographical note

Funding Information:
This work was supported by NIH R01AI149801 to AJC, NIH K08AI108791 to AJC, NIH-DA039005 to PJG, NIH-DA049227 to PJG. The authors would like to thank Alexis Brantly for assisting with CX7 image processing.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Society for Mucosal Immunology.


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