# Role of Tollip in dysfunction of asthma airway innate immunity

> **NIH NIH U19** · UNIVERSITY OF ARIZONA · 2020 · $317,000

## Abstract

Project Summary/Abstract:
The goal of this project is to determine the role of Toll-interacting protein (Tollip) in regulating lung defense
against rhinovirus infection related to asthma exacerbations. Tollip has been proposed as a negative immune
regulator for host defense against bacterial infections. It is widely expressed by various types of cells, including
lung epithelial cells. Tollip single nucleotide polymorphisms (SNPs) have been identified, but the role of Tollip
in asthma has not been investigated. We found that Tollip rs5743899 AG genotype is more frequent in
asthmatics than normal controls. Importantly, asthmatics with the AG genotype demonstrate lower lung
function than asthmatics with the AA genotype. Moreover, human airway epithelial cells carrying the AG
genotype express less Tollip than the AA genotype. The combination of type 2 cytokine IL-13 and rhinovirus
further decreases Tollip expression. Epithelial cells carrying the AG genotype demonstrate, when treated with
IL-13 and rhinovirus (RV), a stronger pro-inflammatory response, but weaker anti-viral response. We therefore
hypothesize that reduction of Tollip in a subset of genetically defined asthmatics, especially in the
setting of type 2 inflammation and viral infection, exaggerates airway inflammation and asthma
severity.
Aim 1 will determine the role of Tollip rs5743899 in asthma lung inflammation, infection and function. By using
brushed human bronchial and nasal epithelial cells and bronchoalveolar lavage fluid from asthmatics and
normal subjects, we will measure Tollip expression, inflammatory and anti-viral responses, and rhinovirus
burden. These data along with the surfactant protein A2 (SP-A2) genetic variant data will then be correlated
with asthma lung function and disease severity.
Aim 2 will determine mechanisms by which Tollip regulates inflammation and viral infection in asthma. By
using primary human bronchial and nasal epithelial cell cultures, and Tollip and autophagy gene knockout
mouse models of allergen exposure and rhinovirus infection, we will test the hypothesis that in a type 2
cytokine milieu, Tollip inhibits the Toll-like receptor (TLR) signaling and pro-inflammatory cytokine production,
but enhances the anti-viral response via enhancing the autophagy activity.
Aim 3 will determine cooperation of Tollip and SP-A in airway defense against viral infections. By using SP-A
and Tollip knockout and transgenic mouse models of allergen exposure and rhinovirus infection, we will test
the hypothesis that Tollip cooperates with SP-A to inhibit airway viral infections in asthma. SP-A maintains or
increases Tollip levels, which in turn further decreases airway inflammation and viral infection.
 Successful completion of Project 2 will deepen our understanding of airway innate immunity dysfunction in
asthma. The role of Tollip in asthma is not known and may act in concert with SP-A to further modulate
response to RV during asthma exacerbations. Unraveling Tollip ...

## Key facts

- **NIH application ID:** 9971438
- **Project number:** 5U19AI125357-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Hong W Chu
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $317,000
- **Award type:** 5
- **Project period:** — → 2021-08-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971438

## Citation

> US National Institutes of Health, RePORTER application 9971438, Role of Tollip in dysfunction of asthma airway innate immunity (5U19AI125357-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9971438. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*