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

• DOI: 10.1016/j.isci.2023.108763
• Publication Date: 2023-12-19T01:04:51Z
• Authors: 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
• Keywords: 0301 basic medicine; 0303 health sciences; Molecular biology; Science; Q; 570 Life sciences; biology; 10184 Institute of Veterinary Pathology; Omics; Transcriptomics;; Article

ABSTRACTRespiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. However, our knowledge of the host pathways that define susceptibility to RSV infection and disease severity is limited. Hypoxia inducible factors (HIFs) define cellular metabolic processes in response to low oxygen and are recognised to play a key role in regulating inflammatory responses in the lower respiratory tract. We demonstrate a role for hypoxia inducible factors (HIFs) to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors significantly reduce expression of the RSV entry receptor nucleolin and inhibit viral driven 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 treating this respiratory pathogen.