# Interplay between canonical and non-canonical interferons in defense against respiratory viruses

> **NIH NIH R21** · YALE UNIVERSITY · 2024 · $251,250

## Abstract

Respiratory viruses have wide-ranging impacts on public health. Impactful viruses include SARS-CoV-2,
which caused over 1.1 million deaths in the U.S. since 2020, influenza, which typically causes tens of thousands
of deaths and hundreds of thousands of hospitalizations each winter, and rhinovirus, which is a major cause of
disease exacerbations in common chronic lung diseases such as asthma and COPD. The interferon (IFN)
response is a critical defense mechanism that protects against these and other respiratory viruses, but excessive
IFN responses can impair tissue repair and drive immunopathology. Canonical Type I (IFNs a, b) and Type III
IFNs (IFNl1-3), are regulated by induction: they are constitutively off but are rapidly and transiently induced in
response to viral infection. This project focuses on a non-canonical Type I interferon, IFN epsilon (IFNe), and its
distinct regulation and role in coordinating mucosal interferon responses in the human respiratory tract.
 IFNe is known to play a role in mucosal defense in the female reproductive tract (FRT), but a role in the
respiratory tract has not previously been described. This project will address this knowledge gap. Our data
indicate that IFNe is constitutively expressed by human airway epithelial cells and can stimulate antiviral
responses in these cells, albeit much less potently than canonical Type I or Type III IFNs. Previous work and our
data also suggest that constitutive IFNe expression is modulated by inflammation. We hypothesize that IFNe
functions to enhance baseline antiviral defenses in the respiratory epithelium, particularly in the setting of recent
damage, thus fine-tuning antiviral responses to be “just enough” to counter infection while minimizing the need
for inducible IFNs and the risk of excessive immune activation upon viral infection. If this model is correct, IFNe
could be the basis of novel strategies to enhance mucosal antiviral defenses while minimizing the risk of
immunopathology from the more potent canonical IFNs. Testing this model supports our long-term goal, to inform
the development of host-directed therapies that reduce the public health impact of respiratory viruses.
 The goal of this project is to establish the presence of IFNe in the human respiratory tract and understand
its relationship to canonical IFNs in regulating and fine-tuning IFN responses. Aim 1 will define the cell-type
specific expression of IFNe in the differentiated human respiratory epithelium and regulators of expression, using
both the tissue-like air-liquid interface culture model and primary human airway mucosal tissue. We will also
define nasopharyngeal (NP) IFNe protein levels in human subjects using NP swabs collected for SARS-CoV-2
screening at Yale New Haven Hospital. Aim 2 will employ the ALI culture model to define the function of IFNe in
the respiratory epithelium alone, in combination with canonical IFNs, and in dynamic setting of viral infection,
testing the impact on high-i...

## Key facts

- **NIH application ID:** 10869077
- **Project number:** 1R21AI182621-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ellen Flescher Foxman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2024-06-17 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869077

## Citation

> US National Institutes of Health, RePORTER application 10869077, Interplay between canonical and non-canonical interferons in defense against respiratory viruses (1R21AI182621-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10869077. Licensed CC0.

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