Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-β or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.

无声缺氧已成为 2019 年冠状病毒病 (COVID-19) 的一个独特特征。在这项研究中，我们发现粘蛋白在 COVID-19 患者的支气管肺泡灌洗液 (BALF) 中积累，并在严重呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的小鼠和猕猴的肺部上调。我们发现，在 SARS-CoV-2 感染时诱导干扰素 (IFN)-β 或 IFN-γ 会导致通过 IDO-Kyn 依赖性途径激活芳烃受体 (AhR) 信号传导，从而导致表达的转录上调粘蛋白，无论是分泌的还是膜结合的，都存在于肺泡上皮细胞中。因此，积累的肺泡粘液会影响血气屏障，从而导致缺氧和肺活量减少，这可以通过阻断 AhR 活性来逆转。