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

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...

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Main Authors: Wing, PAC, Prange-Barczynska, M, Cross, A, Crotta, S, Orbegozo Rubio, C, Cheng, X, Harris, JM, Zhuang, X, Johnson, RL, Ryan, KA, Hall, Y, Carroll, MW, Issa, F, Balfe, P, Wack, A, Bishop, T, Salguero, FJ, McKeating, JA
Format: Journal article
Language:English
Published: Public Library of Science 2022
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author Wing, PAC
Prange-Barczynska, M
Cross, A
Crotta, S
Orbegozo Rubio, C
Cheng, X
Harris, JM
Zhuang, X
Johnson, RL
Ryan, KA
Hall, Y
Carroll, MW
Issa, F
Balfe, P
Wack, A
Bishop, T
Salguero, FJ
McKeating, JA
author_facet Wing, PAC
Prange-Barczynska, M
Cross, A
Crotta, S
Orbegozo Rubio, C
Cheng, X
Harris, JM
Zhuang, X
Johnson, RL
Ryan, KA
Hall, Y
Carroll, MW
Issa, F
Balfe, P
Wack, A
Bishop, T
Salguero, FJ
McKeating, JA
author_sort Wing, PAC
collection OXFORD
description 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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spelling oxford-uuid:23a3ecd6-87b6-413b-8435-f1356202498f2022-10-31T06:36:00ZHypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 modelJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:23a3ecd6-87b6-413b-8435-f1356202498fEnglishSymplectic ElementsPublic Library of Science2022Wing, PACPrange-Barczynska, MCross, ACrotta, SOrbegozo Rubio, CCheng, XHarris, JMZhuang, XJohnson, RLRyan, KAHall, YCarroll, MWIssa, FBalfe, PWack, ABishop, TSalguero, FJMcKeating, JAUnderstanding 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.
spellingShingle Wing, PAC
Prange-Barczynska, M
Cross, A
Crotta, S
Orbegozo Rubio, C
Cheng, X
Harris, JM
Zhuang, X
Johnson, RL
Ryan, KA
Hall, Y
Carroll, MW
Issa, F
Balfe, P
Wack, A
Bishop, T
Salguero, FJ
McKeating, JA
Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model
title Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model
title_full Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model
title_fullStr Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model
title_full_unstemmed Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model
title_short Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model
title_sort hypoxia inducible factors regulate infectious sars cov 2 epithelial damage and respiratory symptoms in a hamster covid 19 model
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