# Epigenetic Mechanism Reprogramming Mucosal Anti-viral Immunity in Allergic Asthma

> **NIH NIH U01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $681,885

## Abstract

PROJECT SUMMARY/ABSTRACT
Rhinovirus (RV) infections are the most common causes of exacerbations in adults with allergic asthma (AA).
Patients with AA have dysregulated type III interferon (IFNL) and T cell responses to infection, impairing viral
clearance. We have found that allergen exposures silence the epithelial IFN regulatory factor (IRF)1- IFNL
antiviral response and activate expression of the T cell co-inhibitor programmed death ligand (PDL)-1/B7H1.
Our data implicate the Zinc Finger E box (ZEB1) transcription factor in mediating this epigenetic
reprogramming by binding histone methyltransferase (EZH2) and histone acetyltransferase (p300/CBP) in a
promoter-specific context. We will test the hypothesis that epithelial ZEB1 is induced by TGFβ signals
produced by innate-induced remodeling and maintained by immunomodulatory eosinophil action. The
epigenetic actions of ZEB1 silence the IRF1-IFNL response yet upregulate PDL1 to suppress CD8 T cell
activation by recruitment of distinct histone acetyltransferases in specific promoter contexts. Our aims
are to: 1. Determine the mechanism how ZEB1 induces epigenetic silencing of the IRF1-IFNL anti-viral
pathway by allergen-and eosinophil-immunomodulation. We will examine the effect of ZEB1-EZH2
silencing on epigenetic modifications of the IRF1 enhancer/promoter in normal and AA epithelial cells (hAECs)
by precision nuclear run-on (PRO-Seq) and chromatin immunoprecipitation. We will examine the role of ZEB-
EZH2 in eosinophil-modulated suppression of IFNL responses in primary eosinophil co-cultures. These
pathways will be probed in vivo by human ICAM1 transgenic mice with or without CDE remodeling upon RV
infection. We expect the defective IRF/IFNL response will be reversed with ZEB1-EZH2 silencing. 2. Elucidate
the mechanism how ZEB1 upregulates mucosal PD-L1 expression and determine its effects on CD8 T
cell tolerance, RV clearance and AHR. RV-induced expression of PD-L1 will be measured in primary hAECs
after silencing ZEB1-p300/CBP pathway. The effect of PDL1 on CD8-T cell suppression will be tested in co-
culture systems using primary human T cells. We will test the role of PD-L1 in RV clearance in the hICAM1
transgenic mouse model using blocking antibodies (Abs) and validate the upregulation of PD-L1 in bronchial
biopsies of AAs vs normal controls. We expect that PD-L1 inhibition will enhance CD8+ T cell activation and
block AHR. 3. Test the effects of RV16 infection on mucosal IFNL and PD-L1 expression in human
volunteers with or without allergen induced remodeling. We will recruit volunteers with eosinophilic AAs,
allergic rhinitis (AR) and normal controls. We will test the relationship between remodeling induced IRF1/IFNL
and PD-L1 expression in response to infection with recombinant RV16. We expect that IRF1-IFNL response
and CD8+T cell response will be blunted in AAs with active remodeling. This project will significantly advance
our understanding of the epigenetic control of mucosal immun...

## Key facts

- **NIH application ID:** 10072025
- **Project number:** 5U01AI136994-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Allan R. Brasier
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $681,885
- **Award type:** 5
- **Project period:** 2019-02-10 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072025

## Citation

> US National Institutes of Health, RePORTER application 10072025, Epigenetic Mechanism Reprogramming Mucosal Anti-viral Immunity in Allergic Asthma (5U01AI136994-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072025. Licensed CC0.

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