Hypoxia inducible factors regulate pneumovirus replication by enhancing innate immune sensing
Abstract
The immune mechanisms responsible for protection and pathogenesis in pneumoviral infection are not well defined. We demonstrated that pharmacological activation of the hypoxic inducible factor (HIF) signaling axis using daprodustat limited viral replication through enhanced immune signaling. Transcriptomic analysis revealed HIF augmented activation of innate immune response genes, including interferon-stimulated gene 15 ( Isg15 ), in the lung and spleen of mice infected with pneumonia virus of mice (PVM). In human respiratory syncytial virus (hRSV)-infected airway epithelial cells, daprodustat inhibited viral replication and enhanced ISG15 expression in a HIF-dependent manner. Importantly, inhibition of type I interferon signaling or the RIG-I sensing pathway abrogated the antiviral activity of HIF. Moreover, daprodustat increased interferon signaling in response to viral RNA, suggesting that HIF inhibits pneumovirus replication through enhancing viral RNA sensing. Mechanistically, daprodustat reduced N 6 -methyladenosine modification of viral RNA through upregulation of RNA demethylases, promoting detection by innate immune sensors. This study highlights the intricate interplay between hypoxia and antiviral immunity and offers valuable insights into pneumovirus–host interactions and potential therapeutic interventions.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Jiyeon Ha
CAMS Oxford Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Nuffield Department of Medicine, University of Oxford
Parul Sharma
Department of Chemistry
Sammi Ta
Nuffield Department of Medicine, University of Oxford
Senko Tsukuda
Nuffield Department of Medicine, University of Oxford
James M. Harris
Nuffield Department of Medicine, University of Oxford
Rebekah Penrice-Randal
Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Eleanor Bentley
Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Adam Kirby
Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Daniele F. Mega
Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
David A. Matthews
School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol
Peter Balfe
Nuffield Department of Medicine, University of Oxford
Jan Rehwinkel
Anja Kipar
Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
James P. Stewart
Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool
Jane A. McKeating
CAMS Oxford Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Nuffield Department of Medicine, University of Oxford
Peter A. C. Wing
CAMS Oxford Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Nuffield Department of Medicine, University of Oxford