Interferon-Independent Upregulation of Interferon-Stimulated Genes during Human Cytomegalovirus Infection is Dependent on IRF3 Expression
Interferon-Independent Upregulation of Interferon-Stimulated Genes during Human Cytomegalovirus Infection is Dependent on IRF3 Expression
复制标题
DOI：
10.3390/v11030246
复制
发表时间：
2019-03-12
期刊：
影响因子：
4.7
通讯作者：
Slobedman, Barry
中科院分区：
文献类型：
--
作者：
Ashley, Caroline L.;Abendroth, Allison;Slobedman, Barry
I型干扰素（IFN）的抗病毒活性主要由干扰素刺激基因（ISG）介导。当I型IFN与其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）信号传导途径时，实现ISG转录的诱导。最近已经清楚的是，许多病毒能够在不产生I型IFN的情况下直接上调ISG的子集。使用经工程改造以阻断对I型IFN的应答或I型IFN的产生的细胞，在人巨细胞病毒（HCMV）感染的背景下检查IFN非依赖性ISG的调节。发现几种ISG，包括IFIT 1、IFIT 2、IFIT 3、Mx 1、Mx2、CXCL 10和ISG 15在HCMV感染后转录上调，独立于I型IFN启动的JAK-STAT信号传导，但依赖于完整的IRF 3信号传导。ISG 15蛋白调节反映了其转录物的调节，IFN β中和不能完全抑制HCMV感染后ISG 15的表达。此外，在IRF 3敲低CRISPR/Cas-9克隆中，在HCMV感染后没有观察到可检测的ISG 15蛋白表达，表明在人成纤维细胞的HCMV感染期间，ISG表达的IFN非依赖性控制绝对依赖于IRF 3表达。
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 IFN beta 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.