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缺氧诱导因子调节 SARS-CoV-2 感染、上皮损伤和 COVID-19 模型中仓鼠的呼吸道症状。

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

机构信息

Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford United Kingdom.

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

出版信息

PLoS Pathog. 2022 Sep 6;18(9):e1010807. doi: 10.1371/journal.ppat.1010807. eCollection 2022 Sep.

DOI:10.1371/journal.ppat.1010807
PMID:36067210
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9481176/
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.

摘要

了解宿主途径，这些途径定义了对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染和疾病的易感性，对于设计新疗法至关重要。微环境中的氧气水平定义了转录景观，然而，缺氧对动物模型中病毒复制和疾病的影响尚不清楚。在这项研究中，我们确定了缺氧诱导因子（HIF）信号轴在抑制叙利亚仓鼠模型中的 SARS-CoV-2 感染、上皮损伤和呼吸道症状方面的作用。用脯氨酰-羟化酶抑制剂 FG-4592 对 HIF 进行药理学激活，可显著减少上呼吸道和下呼吸道中的传染性病毒。在接受治疗的动物中，鼻和肺上皮细胞的 SARS-CoV-2 RNA 和核衣壳表达减少。转录组学和病理学分析显示上皮损伤减少，纤毛细胞表达增加。我们的研究为 HIF 信号通路在 SARS-CoV-2 复制中的内在抗病毒特性提供了新的见解，这些特性可能适用于其他呼吸道病原体，并确定了新的治疗机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/9cebfe7e16b3/ppat.1010807.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/0b91a31fb85e/ppat.1010807.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/7c7dc4680e23/ppat.1010807.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/5cdfeec127a3/ppat.1010807.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/2d2c3b1f9b41/ppat.1010807.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/04021ee7942e/ppat.1010807.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/9cebfe7e16b3/ppat.1010807.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/0b91a31fb85e/ppat.1010807.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/7c7dc4680e23/ppat.1010807.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/5cdfeec127a3/ppat.1010807.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/2d2c3b1f9b41/ppat.1010807.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/04021ee7942e/ppat.1010807.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bbf/9481176/9cebfe7e16b3/ppat.1010807.g006.jpg

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