Department of Infectious Diseases and Immunology, Charles Perkins Centre, University of Sydney, Camperdown, New South Wales 2050, Australia.
Viruses. 2019 Mar 12;11(3):246. doi: 10.3390/v11030246.
The antiviral activity of type I interferons (IFNs) is primarily mediated by interferon-stimulated genes (ISGs). Induction of ISG transcription is achieved when type I IFNs bind to their cognate receptor and activate the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Recently it has become clear that a number of viruses are capable of directly upregulating a subset of ISGs in the absence of type I IFN production. Using cells engineered to block either the response to, or production of type I IFN, the regulation of IFN-independent ISGs was examined in the context of human cytomegalovirus (HCMV) infection. Several ISGs, including IFIT1, IFIT2, IFIT3, Mx1, Mx2, CXCL10 and ISG15 were found to be upregulated transcriptionally following HCMV infection independently of type I IFN-initiated JAK-STAT signaling, but dependent on intact IRF3 signaling. ISG15 protein regulation mirrored that of its transcript with IFNβ neutralization failing to completely inhibit ISG15 expression post HCMV infection. In addition, no detectable ISG15 protein expression was observed following HCMV infection in IRF3 knockdown CRISPR/Cas-9 clones indicating that IFN-independent control of ISG expression during HCMV infection of human fibroblasts is absolutely dependent on IRF3 expression.
I 型干扰素 (IFN) 的抗病毒活性主要是通过干扰素刺激基因 (ISG) 介导的。当 I 型 IFN 与它们的同源受体结合并激活 Janus 激酶/信号转导和转录激活因子 (JAK/STAT) 信号通路时，ISG 的转录就会被诱导。最近已经清楚，许多病毒能够在不产生 I 型 IFN 的情况下直接上调一组特定的 ISG。利用工程细胞来阻断 I 型 IFN 的反应或产生，在人巨细胞病毒 (HCMV) 感染的情况下，研究了 IFN 非依赖性 ISG 的调节。发现几种 ISG，包括 IFIT1、IFIT2、IFIT3、Mx1、Mx2、CXCL10 和 ISG15，在 HCMV 感染后独立于 I 型 IFN 启动的 JAK-STAT 信号转导而上调转录，但依赖于完整的 IRF3 信号转导。ISG15 蛋白的调节与其转录物相似，用 IFNβ 中和并不能完全抑制 HCMV 感染后 ISG15 的表达。此外，在 IRF3 敲低的 CRISPR/Cas-9 克隆中，在 HCMV 感染后没有观察到可检测到的 ISG15 蛋白表达，这表明在 HCMV 感染人成纤维细胞时，IFN 非依赖性 ISG 表达的控制绝对依赖于 IRF3 的表达。
