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: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010807&type=printable |
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| author | Peter A C Wing Maria Prange-Barczynska Amy Cross Stefania Crotta Claudia Orbegozo Rubio Xiaotong Cheng James M Harris Xiaodong Zhuang Rachel L Johnson Kathryn A Ryan Yper Hall Miles W Carroll Fadi Issa Peter Balfe Andreas Wack Tammie Bishop Francisco J Salguero Jane A McKeating |
| author_facet | Peter A C Wing Maria Prange-Barczynska Amy Cross Stefania Crotta Claudia Orbegozo Rubio Xiaotong Cheng James M Harris Xiaodong Zhuang Rachel L Johnson Kathryn A Ryan Yper Hall Miles W Carroll Fadi Issa Peter Balfe Andreas Wack Tammie Bishop Francisco J Salguero Jane A McKeating |
| author_sort | Peter A C Wing |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-3c410b7e7d0e4ff392b4c3a2e70b9525 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2022-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-3c410b7e7d0e4ff392b4c3a2e70b95252025-08-20T03:44:46ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-09-01189e101080710.1371/journal.ppat.1010807Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model.Peter A C WingMaria Prange-BarczynskaAmy CrossStefania CrottaClaudia Orbegozo RubioXiaotong ChengJames M HarrisXiaodong ZhuangRachel L JohnsonKathryn A RyanYper HallMiles W CarrollFadi IssaPeter BalfeAndreas WackTammie BishopFrancisco J SalgueroJane A McKeatingUnderstanding 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010807&type=printable |
| spellingShingle | Peter A C Wing Maria Prange-Barczynska Amy Cross Stefania Crotta Claudia Orbegozo Rubio Xiaotong Cheng James M Harris Xiaodong Zhuang Rachel L Johnson Kathryn A Ryan Yper Hall Miles W Carroll Fadi Issa Peter Balfe Andreas Wack Tammie Bishop Francisco J Salguero Jane A McKeating Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model. PLoS Pathogens |
| 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 |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010807&type=printable |
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