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)-p or IFN-y 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.