Type I and Type II Interferons Inhibit the Translation of Murine Norovirus Proteins
Type I and Type II Interferons Inhibit the Translation of Murine Norovirus Proteins
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DOI：
10.1128/jvi.00231-09
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发表时间：
2009-06-01
影响因子：
5.4
通讯作者：
Karst, Stephanie M.
中科院分区：
文献类型：
--
作者：
Changotra, Harish;Jia, Yali;Karst, Stephanie M.
人类诺如病毒是全世界95%以上的非细菌性流行性胃肠炎的罪魁祸首。疾病症状的发作和消退都是迅速的，这表明先天免疫反应的组成部分在诺如病毒控制中至关重要。虽然由于缺乏小动物和组织培养系统，人类诺如病毒的研究受到阻碍，但我们最近发现的小鼠诺如病毒（MNV）及其体外繁殖使我们能够开始研究诺如病毒的复制策略和对诺如病毒感染的免疫反应。我们之前已经证明，干扰素反应对于控制体内MNV-1感染和直接抑制体外病毒复制至关重要。我们现在扩展这些研究，以确定干扰素介导的抑制的分子基础。在感染或转染病毒粒子相关RNA后，在I型干扰素预处理的允许细胞中未检测到病毒复制中间体，这表明在病毒进入和脱壳后，病毒粒子产生的早期阻断。在感染的原代巨噬细胞和用I型IFN预处理的树突状细胞中，也观察到类似的病毒复制中间体的缺失。这不是由于干扰素预处理细胞中传入基因组的降解，因为未经处理和预处理的细胞在感染6小时后存在相似水平的基因组，并且这些基因组保持其完整性。令人惊讶的是，这种对病毒蛋白翻译的阻断并不依赖于已知的干扰素诱导的抗病毒分子PKR。在II型干扰素预处理的细胞中观察到类似的结果，除了病毒翻译的抑制依赖于PKR。因此，I型和II型干扰素信号都抑制诺如病毒在容许髓细胞中的翻译，但它们表现出明显依赖PKR来抑制这种抑制。
Human noroviruses are responsible for more than 95% of nonbacterial epidemic gastroenteritis worldwide. Both onset and resolution of disease symptoms are rapid, suggesting that components of the innate immune response are critical in norovirus control. While the study of the human noroviruses has been hampered by the lack of small animal and tissue culture systems, our recent discovery of a murine norovirus (MNV) and its in vitro propagation have allowed us to begin addressing norovirus replication strategies and immune responses to norovirus infection. We have previously demonstrated that interferon responses are critical to control MNV-1 infection in vivo and to directly inhibit viral replication in vitro. We now extend these studies to define the molecular basis for interferon-mediated inhibition. Viral replication intermediates were not detected in permissive cells pretreated with type I interferon after either infection or transfection of virion-associated RNA, demonstrating a very early block to virion production that is after virus entry and uncoating. A similar absence of viral replication intermediates was observed in infected primary macrophages and dendritic cells pretreated with type I IFN. This was not due to degradation of incoming genomes in interferon-pretreated cells since similar levels of genomes were present in untreated and pretreated cells through 6 h of infection, and these genomes retained their integrity. Surprisingly, this block to the translation of viral proteins was not dependent on the well-characterized interferon-induced antiviral molecule PKR. Similar results were observed in cells pretreated with type II interferon, except that the inhibition of viral translation was dependent on PKR. Thus, both type I and type II interferon signaling inhibit norovirus translation in permissive myeloid cells, but they display distinct dependence on PKR for this inhibition.