Drake, M. G. | Search bioRxiv

bioRxiv2026

Muc5ac mediates anti-viral immunity and virus-induced parasympathetic nerve dysfunction

Respiratory viruses can induce excessive bronchoconstriction in both asthmatic and healthy airways. Airway mucins such as Muc5ac form the first line of defense against inhaled pathogens. However, when produced in excess, they can also contribute to airway narrowing and mucus plug formation in asthma. In this study, we investigated the role of airway mucins in host defense against parainfluenza virus and in virus-induced airway hyperresponsiveness using Muc5ac-deficient (Muc5ac-/-) C57BL/6 mice. Parainfluenza virus infection induced airway hyperresponsiveness to inhaled methacholine in wild-type mice, an effect that was abolished in Muc5ac-/- mice. Parainfluenza virus-induced airway hyperresponsiveness was reversed by vagotomy, demonstrating it is mediated by parasympathetic nerve dysfunction. Muc5ac-/- mice exhibited higher viral titers, increased bronchoalveolar lavage cellularity, and elevated antiviral cytokine levels, but did not develop airway hyperresponsiveness. We did not see mucus plugging in any of our animals. Together, these findings indicate that Muc5ac is important for host defense against parainfluenza virus but paradoxically is also required for virus-induced airway hyperresponsiveness.

physiology↗

bioRxiv2022

Grandmaternal allergen exposure causes distinct epigenetic trajectories in offspring associated with airway hyperreactivity and inflammation.

Maternal asthma increases childhood asthma risk through multiple mechanisms including epigenetic regulation of asthma-associated genes. DNA methylation is one form of epigenetic regulation that is both inherited and modified by environmental exposures throughout life. In this study, we tested whether grandmaternal house dust mite (HDM) allergen exposure altered airway physiology and inflammation, as well as DNA methylation in both airway epithelium and airway sensory neurons of second-generation offspring. Grandmaternal allergen exposure induced a limited number of epigenetic changes in offspring at baseline that were not associated with increased airway reactivity or inflammation. In contrast, grandmaternal allergen exposure significantly altered offsprings response to HDM sensitization and challenge, inducing airway hyperreactivity to inhaled serotonin, increased airway inflammation, and potentiated DNA methylation. Gene sequences susceptible to methylation after allergen sensitization, and their corresponding biological processes and enriched pathways, were unique in offspring from HDM-exposed founders, indicating that grandmaternal allergen exposure established an epigenetic trajectory in offspring at birth that directed epigenetic and physiologic responses to subsequent allergen sensitization and challenge, contributing to inheritance of asthma risk. SUMMARYGrandmaternal allergen exposure establishes an intergenerational, tissue-specific epigenetic trajectory in offspring at birth, which uniquely directs responses to allergen sensitization and challenge later in life and contributes to inheritance of asthma risk.

physiology↗