Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Lung/enzymology , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors , Binding Sites , COVID-19/genetics , COVID-19/virology , Cell Line , Disease Models, Animal , Host-Pathogen Interactions , Humans , Lung/virology , Macaca , Mice , Promoter Regions, Genetic , Receptors, Aryl Hydrocarbon/geneticsABSTRACT
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)-ß 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.