ABSTRACT We propose to study how the innate response to virus changes as children mature, which we theorize contributes to asthma remission. Although asthma is a chronic disease, its symptoms vary greatly based on the season, time of day, and age. Asthma seasonality is driven by respiratory virus outbreaks2, 3. Time-of-day variations arise from the circadian clock, which regulates lung remodeling after respiratory viral infection4-6. The least understood is why age affects asthma activity, and particularly why asthma exacerbations gradually resolve in 50% of children as they mature7, 8. Understanding the biological processes that cause asthma resolution in children could yield ways of promoting remission in all patients. We hypothesize that asthmatic children experience fewer asthma exacerbations as they age because they develop a pro-resolution response to viruses, preventing new type-2 inflammation and airway remodeling from forming with each new infection. We further hypothesize that circadian clocks operating within alveolar macrophages (AMs) and airway epithelial cells are critical for this pro-resolution response. Our hypotheses arise from observations that, in children, viruses become less potent at triggering asthma exacerbations as children mature. In mice, respiratory viral infections that produce chronic lung remodeling in juvenile animals fail to do so in adults. The protection afforded by adult age correlates with a blunted type 2 inflammatory response to viruses. AMs are required for adult protection from post-viral lung disease and exhibit a distinct transcriptional and immunophenotypic profile. Protection is also marked by reduced accumulation of dysplastic Krt17+ basal cells after respiratory viral infection. Finally, these age-related benefits are negated by circadian clock disruption, leading otherwise protected adult mice to develop chronic post-viral lung disease like juveniles. This project will clarify how the circadian clock mediates the adult age, pro-resolution response to viral asthma triggers. Proposed experiments in mice use Sendai virus (SeV) as a viral model of asthmatic lung remodeling and Alternaria alternata extract as an allergic model that serves as a comparator. We will employ complementary genetic and environmental methods to disrupt circadian clock function (clock gene Bmal1 deletion and chronic jet lag or CJL). Aim 1 focuses on how the adult-age AM clock promotes the resolution of viral inflammation. Aim 2 focuses on how the adult-age epithelial clock promotes the normal repair of viral airway injury. We will analyze antiviral function in airway cells from asthma remission patients for the first time. This project aligns with NIH research priorities and satisfies the recent Notice of Special Interest NOT-HL-22-043: Basic and Translational Research on Circadian Regulation of Heart, Lung, Blood, and Sleep Disorders.