Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.
James & Lillian Martin Centre, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
J Gen Virol. 2023 Aug;104(8). doi: 10.1099/jgv.0.001885.
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 (O), that do not reflect the oxygen levels in most organs (1-5 % O). 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.
I 型干扰素 (IFN) 是宿主抵抗病毒感染的主要防御机制，在细胞表面或细胞内模式识别受体（包括视黄酸诱导基因 I (RIG-I)-样受体 (RLR)）被激活后诱导产生。所有细胞过程都受到微环境的影响，其中一个重要因素是局部氧张力。大多数关于 IFN 信号转导的已发表研究都是在 18%氧 (O) 的实验室条件下进行的，这些条件不能反映大多数器官中的氧水平（1-5% O）。我们研究了低氧对诱导多能干细胞 (iPSC) 衍生巨噬细胞中 IFN 诱导和信号转导的影响，作为组织驻留巨噬细胞的模型，并评估了其对寨卡病毒 (ZIKV) 感染的影响。在早期，低氧条件抑制了 RLR 刺激或 IFN 处理后干扰素刺激基因 (ISG) 的表达。RNA 测序和生物信息学分析揭示了几个途径，包括转录因子可用性的变化、启动子区域中 HIF 结合位点的存在以及 CpG 含量的变化，这些可能有助于降低 ISG 的表达。低氧条件增加了 ZIKV RNA 的丰度，突出了了解局部微环境中低氧条件如何影响病原体感知和宿主防御的重要性。
