Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell Rep. 2018 Sep 11;24(11):3000-3007.e3. doi: 10.1016/j.celrep.2018.08.033.
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.
鼻病毒是急性呼吸道感染和哮喘发作的主要原因，但感染也经常从鼻腔黏膜清除而不引起症状。我们通过研究体外培养的原代人鼻腔和支气管气道上皮细胞中的抗病毒防御机制，试图更好地了解宿主对鼻病毒的防御。令人惊讶的是，鼻病毒感染或 RIG-I 刺激后，鼻腔来源的上皮细胞表现出比支气管来源的细胞更强的抗病毒反应。相反，与鼻腔细胞相比，RIG-I 刺激在支气管细胞中引发了更强的 NRF2 依赖性氧化应激反应激活。NRF2 激活抑制了上皮细胞的抗病毒反应，而 NRF2 敲低增强了抗病毒反应，并在鼻病毒感染期间具有保护作用。这些发现表明，上皮细胞对不同类型的气道损伤（即病毒与氧化）的防御存在权衡，并且揭示了来自不同气道微环境的细胞中防御反应的差异校准。
