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
Affiliations
Xiaodong Zhuang
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Corresponding author
Giulia Gallo
The Pirbright Institute, Guildford, Surrey, UK
Parul Sharma
Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
Jiyeon Ha
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Andrea Magri
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Helene Borrmann
Nuffield Department of Medicine, University of Oxford, Oxford, UK
James M. Harris
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Senko Tsukuda
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Eleanor Bentley
Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
Adam Kirby
Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
Simon de Neck
Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 268, 8057 Zurich, Switzerland
Hongbing Yang
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Peter Balfe
Nuffield Department of Medicine, University of Oxford, Oxford, UK
Peter A.C. Wing
Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
David Matthews
School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, UK
Adrian L. Harris
Oncology Department, University of Oxford, Oxford, UK
Anja Kipar
Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 268, 8057 Zurich, Switzerland
James P. Stewart
Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
Dalan Bailey
The Pirbright Institute, Guildford, Surrey, UK
Jane A. McKeating
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK; Corresponding author
Summary: 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.
