# Mechanisms of regulatory T cell-mediated recovery from severe influenza A virus infection

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $505,528

## Abstract

PROJECT SUMMARY/ABSTRACT
Seasonal influenza is associated with up to 650,000 respiratory deaths per year worldwide. Influenza A virus
injures the lung to cause the acute respiratory distress syndrome (ARDS). Influenza A virus-induced ARDS
carries a mortality rate approaching 40% despite advances in anti-viral therapies and supportive care, with most
patients succumbing to intensive care unit (ICU) complications as they recover from the initial infection. In mice,
dysregulated repair leads to widespread and persistent alveolar epithelial abnormalities following severe
influenza A. We reason that activation of repair pathways during recovery from severe influenza will shorten the
duration of time that patients require the ICU, thus mitigating the ICU’s attendant morbidity and mortality.
CD4+Foxp3+ regulatory T (Treg) cells are required to coordinate resolution of lung inflammation and repair of
lung damage in mouse models. These cells appear in the alveolar spaces of patients with ARDS and display
epigenetic and transcriptional profiles predicted by murine experiments. In the injured lung, Treg cells exert
myriad pro-recovery functions, including generation of pro-epithelial molecules such as amphiregulin, the loss of
which worsens influenza A-induced acute lung injury in mice. Within Treg cells, the DNA methylation pattern at
specific genomic loci controls their identity and suppressive function. The epigenetic regulator protein Uhrf1 plays
an essential role in maintaining cell type-specific DNA methylation signatures. The necessity of Uhrf1 in
maintaining Treg cell identity and pro-repair function during the recovery phase of influenza A remains unknown.
Likewise, the necessity of amphiregulin in inducing healthy epithelial repair during the recovery phase is also
undefined. We hypothesize that Treg cells require Uhrf1 to maintain their pro-repair function and
amphiregulin to induce epithelial repair during recovery from severe influenza A virus infection. We
propose three Specific Aims, which use innovative approaches to test our hypothesis, including cutting-edge
murine systems, novel computational platforms, and a human case-control study that will translate our findings
to the bedside. Aim 1 will determine whether Uhrf1 is necessary to maintain Treg cell transcriptional programs
and pro-repair function during recovery from influenza A. Aim 2 will ascertain the necessity of Treg cell-generated
amphiregulin in promoting repair during recovery from influenza A-induced lung injury. Aim 3 will determine
whether transcriptional and epigenetic signatures in alveolar Treg cells are associated with 30-day mortality in
selected patients with severe viral pneumonia. Our proposal will establish causal evidence linking drug-
targetable mechanisms to detailed physiologic readouts. Elucidating these causal links will inform the
development of pro-recovery therapeutic approaches for severe influenza and other causes of ARDS.

## Key facts

- **NIH application ID:** 9865260
- **Project number:** 1R01HL149883-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Benjamin David Singer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,528
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865260

## Citation

> US National Institutes of Health, RePORTER application 9865260, Mechanisms of regulatory T cell-mediated recovery from severe influenza A virus infection (1R01HL149883-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9865260. Licensed CC0.

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