Volume 30, No 12, Dec 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 12, December 2020: 1078-1087   |  Open Access

ORIGINAL ARTICLES

Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19

Yuying Liu^1,2 , Jiadi Lv¹ , Jiangning Liu³ , Man Li⁴ , Jing Xie¹ , Qi Lv³ , Wei Deng³ , Nannan Zhou¹ , Yabo Zhou¹ , Jiangping Song⁵ , Peng Wang⁴ , Chuan Qin³ , Wei-Min Tong⁶ , Bo Huang^1,2,7,*

¹Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China
²Clinical Immunology Center, CAMS, Beijing 100005, China
³NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, CAMS and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
⁴Department of Pathology, Beijing Ditan Hospital, Capital Medical University, No.8 Jing Shun East Street, Chaoyang District, Beijing 100015, China
⁵State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, CAMS and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, China
⁶Department of Pathology, Institute of Basic Medical Sciences, CAMS and Peking Union Medical College, Beijing 100005, China
⁷Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430030, China
These authors contributed equally: Yuying Liu, Jiadi Lv Correspondence: Bo Huang(tjhuangbo@hotmail.com)

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.

https://doi.org/10.1038/s41422-020-00435-z

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