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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Bibliographic Details
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
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1010807