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Type I interferons (IFNs) are the major host defence against viral infection and are induced following activation of cell surface or intracellular pattern recognition receptors, including retinoic-acid-inducible gene I (RIG-I)-like receptors (RLRs). All cellular processes are shaped by the microenvironment and one important factor is the local oxygen tension. The majority of published studies on IFN signalling are conducted under laboratory conditions of 18% oxygen (O2), that do not reflect the oxygen levels in most organs (1-5 % O2). We studied the effect of low oxygen on IFN induction and signalling in induced Pluripotent Stem Cell (iPSC)-derived macrophages as a model for tissue-resident macrophages and assessed the consequence for Zika virus (ZIKV) infection. Hypoxic conditions dampened the expression of interferon-stimulated genes (ISGs) following RLR stimulation or IFN treatment at early time points. RNA-sequencing and bio-informatic analysis uncovered several pathways including changes in transcription factor availability, the presence of HIF binding sites in promoter regions, and CpG content that may contribute to the reduced ISG expression. Hypoxic conditions increased the abundance of ZIKV RNA highlighting the importance of understanding how low oxygen conditions in the local microenvironment affect pathogen sensing and host defences.

Original publication

DOI

10.1099/jgv.0.001885

Type

Journal article

Journal

The Journal of general virology

Publication Date

08/2023

Volume

104

Addresses

Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.

Keywords

Macrophages, Humans, Oxygen, Interferon Type I, Receptors, Immunologic, RNA, Immunity, Innate, Induced Pluripotent Stem Cells, Zika Virus, Zika Virus Infection, Hypoxia, DEAD Box Protein 58