# Tuft Cells Modulate Macrophage Response Following Lung Viral Infection

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $243,000

## Abstract

ABSTRACT
The hyperinflammatory response is a major cause of disease severity and death in patients infected by influenza or SARS-
CoV-2. In severe cases dysregulated macrophage responses contribute to the progression of acute respiratory distress
syndrome (ARDS). Nevertheless, how macrophages are activated remains largely unknown, especially in COVID-19 lungs.
Intriguingly, we and others found that the immune sensing tuft cells are ectopically present in the alveolar region
(parenchyma) following infection by H1N1 (PR8) virus with unclarified functions. Our preliminary data show that these
tuft cells are derived from ectopic basal cells (also known as pod cells) in the parenchyma. More importantly, tuft cell
reduction and ablation result in reduced macrophage accumulation, improved survival rate and better recovery,
accompanied by the decreased level of Il-25. Pharmacological inhibition of Notch signaling reduces the numbers of ectopic
tuft cells in PR8-infected lungs. These findings lead to the hypothesis that tuft cells enhance macrophage accumulation
through Il-25 and that reducing tuft cell derivation through Notch inhibition attenuates excessive macrophage
responses and improves lung function. We formulate two specific aims to further test the hypothesis. Aim1: To determine
whether tuft cells modulate macrophage responses through Il-25 upon infection with influenza or SARS-CoV-2. We will
also use a novel R26hACE2 mouse line to build the first targeted SARS-CoV-2 infection model. Aim 2: To test the hypothesis
that Notch inhibition reduces tuft cell derivation from pod cells and attenuates macrophage responses in virus-infected
lungs. In this aim, we will delete Rbpjk in pod cells and use a novel Notch decoy to inhibit Notch signaling. Together this
project will provide the first mechanistic insights into the role played by tuft cells in driving dysregulated macrophage
responses in virus-infected lungs. It will also offer new approaches to reduce tuft cell differentiation and attenuate
hyperinflammation.

## Key facts

- **NIH application ID:** 10453066
- **Project number:** 1R21AI163753-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jianwen Que
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453066

## Citation

> US National Institutes of Health, RePORTER application 10453066, Tuft Cells Modulate Macrophage Response Following Lung Viral Infection (1R21AI163753-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10453066. Licensed CC0.

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