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.
Public Health Relevance: This research will establish a novel antiviral pathway in the lung connected to circadian rhythms that is applicable to asthma, and which could be targeted through drugs or behavioral modification. Such therapies could mitigate asthma exacerbations triggered by viral infection, and potentially prevent asthma inception in at-risk young children. This project will have additional applications for mitigating viral bronchiolitis in infants (the most common cause of infant hospitalization), as well as for respiratory infections in long-haul air travelers with jet lag.
|Ehlers, A; Xie, W; Agapov, E et al. (2018) BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes. Mucosal Immunol 11:97-111|