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The differential roles of Type I and Type III interferon signaling in the neonatal response to influenza virus infection
Dissertation

The differential roles of Type I and Type III interferon signaling in the neonatal response to influenza virus infection

Abigail Patricia Onufer
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2026
DOI:
https://doi.org/10.17918/00011331
pdf
Onufer_Abigail_20265.88 MB
PDF Embargoed Access, Embargo ends: 30 Apr 2028

Abstract

Innate immunology Interferons Neonates Influenza
Infants are remarkably susceptible to influenza virus (IV) infections. Type I and type III interferons (IFN-Is and IFN-IIIs) are key components of the innate immune response required for protection in adults. In contrast, using a neonatal murine model of IV infection, our lab has recently shown that IFN-IIIs are the dominant IFN driving neonatal protection, while IFN-Is exacerbated mortality. However, the mechanisms underlying these differential influences are unknown. In the delicate neonatal lung, we hypothesized that IFN-Is and IFN-IIIs exert opposing effects on epithelial and immune cell communication. This relationship is crucial for balancing viral clearance with tissue protection. Using bulk-RNAseq we revealed that IFN-Is inhibited early repair programs within IV-infected neonatal type II epithelial cells, which decreased lung repair and tight junction expression in the whole lung late in infection. To further elucidate the impact IFN-I and IFN-III signaling on epithelial and immune cell interactions, we performed spatial transcriptomics on IV-infected whole lung tissue sections from neonates with IFN signaling intact, and those lacking either IFN-I or IFN-III signaling. Here, IFN-Is induced robust inflammatory programs, alveolar barrier disruption, and neutrophil influx. Notably, loss of IFN-III signaling amplified neutrophil degranulation. When taken together, we find that IFN-I signaling inhibited lung repair, increased alveolar barrier disruption, and drove neutrophil activation in IV-infected neonates. In contrast, IFN-III signaling induced antiviral gene expression while counteracting these pathogenic effects, which supported essential development. This work provides further insight into age-specific responses to respiratory viral infections and importantly identifies therapeutic avenues for this vulnerable population.

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