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Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model.
PLoS Pathog. 2022 09; 18(9):e1010807.PP

Abstract

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.

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Authors+Show Affiliations

Wing PAC
Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford United Kingdom. Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Prange-Barczynska M
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. Ludwig institute for Cancer Research, University of Oxford, Oxford, United Kingdom.
Cross A
Radcliffe Department of Surgery, University of Oxford, United Kingdom.
Crotta S
Immunoregulation Laboratory, The Francis Crick Institute, London, United Kingdom.
Orbegozo Rubio C
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Cheng X
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. Ludwig institute for Cancer Research, University of Oxford, Oxford, United Kingdom.
Harris JM
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Zhuang X
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Johnson RL
United Kingdom Health Security Agency (UKHSA), Porton Down, Salisbury, United Kingdom.
Ryan KA
United Kingdom Health Security Agency (UKHSA), Porton Down, Salisbury, United Kingdom.
Hall Y
United Kingdom Health Security Agency (UKHSA), Porton Down, Salisbury, United Kingdom.
Carroll MW
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Issa F
Radcliffe Department of Surgery, University of Oxford, United Kingdom.
Balfe P
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Wack A
Immunoregulation Laboratory, The Francis Crick Institute, London, United Kingdom.
Bishop T
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. Ludwig institute for Cancer Research, University of Oxford, Oxford, United Kingdom.
Salguero FJ
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. United Kingdom Health Security Agency (UKHSA), Porton Down, Salisbury, United Kingdom.
McKeating JA
Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford United Kingdom. Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

MeSH

AnimalsAntiviral AgentsCOVID-19CricetinaeHypoxiaLungMesocricetusOxygenProlyl-Hydroxylase InhibitorsRNA, ViralSARS-CoV-2

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

36067210

Citation

Wing, Peter A C., et al. "Hypoxia Inducible Factors Regulate Infectious SARS-CoV-2, Epithelial Damage and Respiratory Symptoms in a Hamster COVID-19 Model." PLoS Pathogens, vol. 18, no. 9, 2022, pp. e1010807.
Wing PAC, Prange-Barczynska M, Cross A, et al. Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model. PLoS Pathog. 2022;18(9):e1010807.
Wing, P. A. C., Prange-Barczynska, M., Cross, A., Crotta, S., Orbegozo Rubio, C., Cheng, X., Harris, J. M., Zhuang, X., Johnson, R. L., Ryan, K. A., Hall, Y., Carroll, M. W., Issa, F., Balfe, P., Wack, A., Bishop, T., Salguero, F. J., & McKeating, J. A. (2022). Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model. PLoS Pathogens, 18(9), e1010807. https://doi.org/10.1371/journal.ppat.1010807
Wing PAC, et al. Hypoxia Inducible Factors Regulate Infectious SARS-CoV-2, Epithelial Damage and Respiratory Symptoms in a Hamster COVID-19 Model. PLoS Pathog. 2022;18(9):e1010807. PubMed PMID: 36067210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model. AU - Wing,Peter A C, AU - Prange-Barczynska,Maria, AU - Cross,Amy, AU - Crotta,Stefania, AU - Orbegozo Rubio,Claudia, AU - Cheng,Xiaotong, AU - Harris,James M, AU - Zhuang,Xiaodong, AU - Johnson,Rachel L, AU - Ryan,Kathryn A, AU - Hall,Yper, AU - Carroll,Miles W, AU - Issa,Fadi, AU - Balfe,Peter, AU - Wack,Andreas, AU - Bishop,Tammie, AU - Salguero,Francisco J, AU - McKeating,Jane A, Y1 - 2022/09/06/ PY - 2022/05/27/received PY - 2022/08/10/accepted PY - 2022/09/16/revised PY - 2022/9/7/pubmed PY - 2022/9/21/medline PY - 2022/9/6/entrez SP - e1010807 EP - e1010807 JF - PLoS pathogens JO - PLoS Pathog VL - 18 IS - 9 N2 - 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. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/36067210/Hypoxia_inducible_factors_regulate_infectious_SARS_CoV_2_epithelial_damage_and_respiratory_symptoms_in_a_hamster_COVID_19_model_ DB - PRIME DP - Unbound Medicine ER -