In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 9 ( 2022-9-6), p. e1010807-
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010807
DOI:
10.1371/journal.ppat.1010807.g001
DOI:
10.1371/journal.ppat.1010807.g002
DOI:
10.1371/journal.ppat.1010807.g003
DOI:
10.1371/journal.ppat.1010807.g004
DOI:
10.1371/journal.ppat.1010807.g005
DOI:
10.1371/journal.ppat.1010807.g006
DOI:
10.1371/journal.ppat.1010807.s001
DOI:
10.1371/journal.ppat.1010807.s002
DOI:
10.1371/journal.ppat.1010807.s003
DOI:
10.1371/journal.ppat.1010807.s004
DOI:
10.1371/journal.ppat.1010807.s005
DOI:
10.1371/journal.ppat.1010807.s006
DOI:
10.1371/journal.ppat.1010807.s007
DOI:
10.1371/journal.ppat.1010807.s008
DOI:
10.1371/journal.ppat.1010807.s009
DOI:
10.1371/journal.ppat.1010807.s010
DOI:
10.1371/journal.ppat.1010807.s011
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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