# Clock Gene Control of Viral Infection and Asthma

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $527,404

## Abstract

PROJECT SUMMARY
Asthma is a common lung disorder whose activity is strongly influenced by time. Asthma symptoms vary with
the season (reflecting rates of respiratory viral infection), and they also vary by the time of day, such that many
patients experience their worst symptoms in the middle of the night. The latter suggests that the circadian clock,
a collection of genes that produce circadian rhythms, is connected to asthma. While viruses and circadian
rhythms are both known to affect asthma symptoms, these two aspects of disease have never been
mechanistically linked. Here, we discovered that a circadian clock gene called bmal1 may impact asthma by
regulating the lung’s response to common respiratory viruses. We show that disruption of the clock gene bmal1
in mice produces an aberrant antiviral response to parainfluenza and influenza A viruses, resulting in severe
lower respiratory tract infection. The antiviral actions of bmal1 appear localized to airway epithelial cells, where
this gene orchestrates interferon responses during acute viral illness. After the acute infection resolves, we show
in mice that bmal1 deficiency exacerbates post-viral chronic airway disease, including features that are
characteristic of asthmatic lungs. Finally, we found that bmal1 expression is down-regulated in airway samples
from asthma patients. Based on these data, we hypothesize that the circadian clock regulates the antiviral
responses of airway epithelial cells through bmal1, and thereby controls the severity of acute and chronic viral
lung pathology. We further hypothesize that circadian clock function is defective in the airway epithelial cells of
asthmatics, leading to reduced bmal1 expression, and potentially explaining the heightened susceptibility that
these patients have to respiratory viruses. To determine the mechanism by which bmal1 mediates antiviral
defenses in the respiratory system we propose the following Specific Aims: 1) Determine how bmal1 in airway
epithelial cells controls interferon gene expression and the severity of acute respiratory viral illness in
mice; 2) Determine how bmal1 deficiency promotes post-viral chronic airway disease in mice; and, 3)
Determine the nature of the circadian clock dysfunction in the airway epithelium of asthmatic
patients. We will address Aim1 by using airway-conditional bmal1 knockout mice and in vitro culture of bmal1-
null mouse tracheal epithelial cells to delineate how this gene regulates the interferon response to respiratory
viruses (Sendai and Influenza A viruses). We will address Aim 2 by using tamoxifen-inducible bmal1 knockout
mice to define when in the course of infection bmal1 is needed for the regulation of post-viral lung disease. We
will address Aim 3 by using a luciferase reporter system to analyze circadian clock function and bmal1 expression
in cultured human airway cells, derived from normal and asthmatic subjects.

## Key facts

- **NIH application ID:** 10064005
- **Project number:** 5R01HL135846-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jeffrey Adam Haspel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $527,404
- **Award type:** 5
- **Project period:** 2016-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064005

## Citation

> US National Institutes of Health, RePORTER application 10064005, Clock Gene Control of Viral Infection and Asthma (5R01HL135846-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064005. Licensed CC0.

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