| Summary: | Summary: Rhinovirus is a leading cause of acute respiratory infections and asthma attacks, but infections are also frequently cleared from the nasal mucosa without causing symptoms. We sought to better understand host defense against rhinovirus by investigating antiviral defense in primary human nasal and bronchial airway epithelial cells cultured ex vivo. Surprisingly, upon rhinovirus infection or RIG-I stimulation, nasal-derived epithelial cells exhibited much more robust antiviral responses than bronchial-derived cells. Conversely, RIG-I stimulation triggered more robust activation of the NRF2-dependent oxidative stress response in bronchial cells compared to nasal cells. NRF2 activation dampened epithelial antiviral responses, whereas NRF2 knockdown enhanced antiviral responses and was protective during rhinovirus infection. These findings demonstrate a tradeoff in epithelial defense against distinct types of airway damage, namely, viral versus oxidative, and reveal differential calibration of defense responses in cells derived from different airway microenvironments. : Airway epithelial cells form the first line of defense against harmful substances that enter the airway. Mihaylova et al. show that viral RNA detection triggers both the NRF2-mediated oxidative stress response and the antiviral interferon response in epithelial cells and demonstrates a tradeoff between these defense responses. Keywords: rhinovirus, NRF2, RIG-I, innate immunity, oxidative stress, airway epithelial cells, HNEC, HBEC, cigarette smoke, sulforaphane
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