Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model

• Published in: PLoS pathogens 2022-09, Vol.18 (9), p.e1010807
• Main Authors: Wing, Peter A C, Prange-Barczynska, Maria, Cross, Amy, Crotta, Stefania, Orbegozo Rubio, Claudia, Cheng, Xiaotong, Harris, James M, Zhuang, Xiaodong, Johnson, Rachel L, Ryan, Kathryn A, Hall, Yper, Carroll, Miles W, Issa, Fadi, Balfe, Peter, Wack, Andreas, Bishop, Tammie, Salguero, Francisco J, McKeating, Jane A
• Format: Article
• Language: English
• Subjects: Animal diseases; Animal models; Animals; Antiviral activity; Antiviral Agents; Biology and life sciences; Body temperature; Coronaviruses; COVID-19; Cricetinae; Damage; Drug dosages; Enzymes; Gene expression; Hydroxylase; Hypoxia; Infections; Influenza; Lung - pathology; Lungs; Medicine and health sciences; Mesocricetus; Microenvironments; Nucleocapsids; Oxygen; Pathogens; Physiology; Prolyl-Hydroxylase Inhibitors; Replication; Respiratory diseases; Respiratory tract; RNA, Viral; Rodents; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal transduction; Signaling; Signs and symptoms; Transcriptomics; Viral diseases; Viral infections; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010807

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.