Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

Xiaodong Zhuang; Giulia Gallo; Parul Sharma; Jiyeon Ha; Andrea Magri; Helene Borrmann; James M Harris; Senko Tsukuda; Eleanor Bentley; Adam Kirby; Simon de Neck; Hongbing Yang; Peter Balfe; Peter A C Wing; David Matthews; Adrian L Harris; Anja Kipar; James P Stewart; Dalan Bailey; Jane A McKeating

doi:10.1016/j.isci.2023.108763

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

iScience. 2023 Dec 18;27(1):108763. doi: 10.1016/j.isci.2023.108763. eCollection 2024 Jan 19.

Authors

Xiaodong Zhuang¹, Giulia Gallo², Parul Sharma³, Jiyeon Ha¹, Andrea Magri¹, Helene Borrmann¹, James M Harris¹, Senko Tsukuda¹, Eleanor Bentley³, Adam Kirby³, Simon de Neck⁴, Hongbing Yang¹, Peter Balfe¹, Peter A C Wing⁵, David Matthews⁶, Adrian L Harris⁷, Anja Kipar^{3

4}, James P Stewart³, Dalan Bailey², Jane A McKeating^{1

5}

Affiliations

¹ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
² The Pirbright Institute, Guildford, Surrey, UK.
³ Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
⁴ Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 268, 8057 Zurich, Switzerland.
⁵ Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.
⁶ School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, UK.
⁷ Oncology Department, University of Oxford, Oxford, UK.

Abstract

Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. Hypoxia inducible factors (HIFs) define metabolic responses to low oxygen and regulate inflammatory responses in the lower respiratory tract. We demonstrate a role for HIFs to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors reduce the expression of the RSV entry receptor nucleolin and inhibit viral cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for this respiratory pathogen.

Keywords: Molecular biology; Omics; Transcriptomics;.

Abstract

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