The Alpha/Beta Interferon Receptor Provides Protection against Influenza Virus Replication but Is Dispensable for Inflammatory Response Signaling
The Alpha/Beta Interferon Receptor Provides Protection against Influenza Virus Replication but Is Dispensable for Inflammatory Response Signaling
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DOI：
10.1128/jvi.01595-09
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发表时间：
2010-02-15
影响因子：
5.4
通讯作者：
Katze, Michael G.
中科院分区：
文献类型：
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作者：
Goodman, Alan G.;Zeng, Hui;Katze, Michael G.
先天免疫反应通过对外来病原体做出反应，提供第一道防线，这些分子是病原体感染的特征。某些RNA病毒，例如流感病毒，在复制生命周期中产生双链RNA作为中间体，其激活能够诱导干扰素产生的病原体识别受体。通过与干扰素受体结合，干扰素激活 JAK-STAT 通路，导致干扰素产生的正反馈，从而增强对病毒感染的反应。为了研究干扰素信号传导缺陷如何影响细胞对感染的反应，我们对缺乏α/β干扰素受体、γ干扰素受体或两者的小鼠胚胎成纤维细胞进行了流感病毒感染。在缺乏 α/β 干扰素受体的情况下，我们观察到病毒复制增加，但 PKR、Stat1 和 NF-κ B 的激活减少； γ干扰素受体的存在或不存在在这些读数中没有表现出明显的差异。基因表达谱分析表明，虽然缺乏α/β干扰素受体的细胞表现出抗病毒基因转录水平降低，但与炎症和凋亡反应相关的基因转录水平与含有该受体的细胞相似。这些结果表明，虽然需要α/β干扰素受体来抑制病毒复制，但它对于诱导某些炎症和凋亡基因是可有可无的。我们已经确定了通过干扰素调节因子 3 (IRF3) 激活或 Hoxa13、Polr2a、Nr4a1 或 Ing1 诱导导致这种冗余的潜在途径。这项研究说明了宿主进化建立几种重叠机制来应对病毒感染的另一种方式。
The innate immune response provides the first line of defense against foreign pathogens by responding to molecules that are a signature of a pathogenic infection. Certain RNA viruses, such as influenza virus, produce double-stranded RNA as an intermediate during the replication life cycle, which activates pathogen recognition receptors capable of inducing interferon production. By engaging interferon receptors, interferon activates the JAK-STAT pathway and results in the positive feedback of interferon production, amplifying the response to viral infection. To examine how deficiencies in interferon signaling affect the cellular response to infection, we performed influenza virus infections of mouse embryonic fibroblasts lacking the alpha/beta interferon receptor, the gamma interferon receptor, or both. In the absence of the alpha/beta interferon receptor, we observed increased viral replication but decreased activation of PKR, Stat1, and NF-kappa B; the presence or absence of the gamma interferon receptor did not exhibit discernible differences in these readouts. Analysis of gene expression profiles showed that while cells lacking the alpha/beta interferon receptor exhibited decreased levels of transcription of antiviral genes, genes related to inflammatory and apoptotic responses were transcribed to levels similar to those of cells containing the receptor. These results indicate that while the alpha/beta interferon receptor is needed to curb viral replication, it is dispensable for the induction of certain inflammatory and apoptotic genes. We have identified potential pathways, via interferon regulatory factor 3 (IRF3) activation or Hoxa13, Polr2a, Nr4a1, or Ing1 induction, that contribute to this redundancy. This study illustrates another way in which the host has evolved to establish several overlapping mechanisms to respond to viral infections.