Differential Delivery of Genomic Double-Stranded RNA Causes Reovirus Strain-Specific Differences in Interferon Regulatory Factor 3 Activation.
Differential Delivery of Genomic Double-Stranded RNA Causes Reovirus Strain-Specific Differences in Interferon Regulatory Factor 3 Activation.
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基因组双链 RNA 的差异传递导致呼肠孤病毒株特异性的干扰素调节因子 3 激活差异。
DOI：
10.1128/jvi.01947-17
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发表时间：
2018
影响因子：
5.4
通讯作者：
Boehme,KarlW
中科院分区：
文献类型：
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作者：
Stuart,JohnashaD;Holm,GeoffreyH;Boehme,KarlW
血清3型（T3）呼肠孤病毒比血清1型（T1）毒株诱导实质上更多的1型干扰素（IFN-I）分泌。然而，T1和T3呼肠孤病毒之间IFN-I产生差异的潜在机制仍不清楚。在这里，我们发现T1和T3呼肠孤病毒之间IFN-I产生的差异与干扰素调节因子3（IRF 3）的激活相关，IRF 3是产生IFN-I的关键转录因子。在猴病毒40（SV 40）永生化内皮细胞（SVECs）中，T3株rsT 3D比T1株rsT 1 L更快地激活IRF 3，并且激活程度更大。rsT 1 L和rsT 3D之间IRF 3激活的差异在感染的最初几个小时内观察到，并且独立于新病毒RNA和蛋白质合成。NF-κB活化反映了IRF 3活化，其中rsT 3D比rsT 1 L诱导更多的NF-κB活性。我们还发现IRF 3和NF-κB以线粒体抗病毒信号蛋白（MAVS）依赖的方式被激活。rsT 1 L不抑制IRF 3活化，因为在rsT 1 L感染的细胞中可以诱导IRF 3磷酸化。转染的rsT 1 L和rsT 3D RNA诱导IRF 3磷酸化，表明来自两种菌株的基因组RNA具有激活IRF 3的能力。最后，通过转染体外产生的病毒核心绕过呼肠孤病毒进入的正常途径显示，rsT 1 L和rsT 3D核心颗粒诱导了等效的IRF 3激活。两者合计，我们的研究结果表明，进入相关的事件发生后，外衣壳解体，但之前的病毒核心沉积到细胞质中，影响的效率IFN-Ⅰ呼肠孤病毒的反应。这项工作提供了进一步深入了解的机制，无包膜病毒激活先天性免疫responses.IMPORTANCEDetection病毒核酸的宿主细胞触发1型干扰素（IFN-I）的反应，这是至关重要的遏制和清除病毒感染。病毒RNA在细胞质中被启动信号传导途径的细胞受体感知，导致干扰素调节因子3（IRF 3）和NF-κB（IFN-I诱导所需的关键转录因子）活化。血清3型（T3）呼肠孤病毒比血清1型（T1）毒株诱导显著更多的IFN-I。在这项工作中，我们发现T1和T3呼肠孤病毒产生IFN-I的差异与差异IRF 3激活相关。IRF 3激活的差异不是由T1菌株阻断IRF 3激活引起的。相反，在病毒进入的晚期阶段期间事件的差异决定了呼肠孤病毒激活宿主IFN-1应答的能力。总之，我们的工作提供了深入了解IFN-I诱导无包膜病毒的机制。
Serotype 3 (T3) reoviruses induce substantially more type 1 interferon (IFN-I) secretion than serotype 1 (T1) strains. However, the mechanisms underlying differences in IFN-I production between T1 and T3 reoviruses remain undefined. Here, we found that differences in IFN-I production between T1 and T3 reoviruses correlate with activation of interferon regulatory factor 3 (IRF3), a key transcription factor for the production of IFN-I. T3 strain rsT3D activated IRF3 more rapidly and to a greater extent than the T1 strain rsT1L, in simian virus 40 (SV40) immortalized endothelial cells (SVECs). Differences in IRF3 activation between rsT1L and rsT3D were observed in the first hours of infection and were independent ofde novoviral RNA and protein synthesis. NF-κB activation mirrored IRF3 activation, with rsT3D inducing more NF-κB activity than rsT1L. We also found that IRF3 and NF-κB are activated in a mitochondrial antiviral-signaling protein (MAVS)-dependent manner. rsT1L does not suppress IRF3 activation, as IRF3 phosphorylation could be induced in rsT1L-infected cells. Transfected rsT1L and rsT3D RNA induced IRF3 phosphorylation, indicating that genomic RNA from both strains has the capacity to activate IRF3. Finally, bypassing the normal route of reovirus entry by transfectingin vitro-generated viral cores revealed that rsT1L and rsT3D core particles induced equivalent IRF3 activation. Taken together, our findings indicate that entry-related events that occur after outer capsid disassembly, but prior to deposition of viral cores into the cytoplasm, influence the efficiency of IFN-I responses to reovirus. This work provides further insight into mechanisms by which nonenveloped viruses activate innate immune responses.IMPORTANCEDetection of viral nucleic acids by the host cell triggers type 1 interferon (IFN-I) responses, which are critical for containing and clearing viral infections. Viral RNA is sensed in the cytoplasm by cellular receptors that initiate signaling pathways, leading to the activation of interferon regulatory factor 3 (IRF3) and NF-κB, key transcription factors required for IFN-I induction. Serotype 3 (T3) reoviruses induce significantly more IFN-I than serotype 1 (T1) strains. In this work, we found that differences in IFN-I production by T1 and T3 reoviruses correlate with differential IRF3 activation. Differences in IRF3 activation are not caused by a blockade of the IRF3 activation by a T1 strain. Rather, differences in events during the late stages of viral entry determine the capacity of reovirus to activate host IFN-I responses. Together, our work provides insight into mechanisms of IFN-I induction by nonenveloped viruses.