Alphavirus infection of fibroblastic cell types in vitro inhibits host cell translation and transcription, leading to suppression of interferon alpha/beta (IFN-α/β) production. However, the effect of infection upon myeloid cells, which are often the first cells encountered by alphaviruses in vivo, is unclear. Previous studies demonstrated an association of systemic IFN-α/β production with myeloid cell infection efficiency. Murine infection with wild-type Venezuelan equine encephalitis virus (VEEV), a highly myeloid-cell-tropic alphavirus, results in secretion of very high systemic levels of IFN-α/β, suggesting that stress responses in responding cells are active. Here, we infected myeloid cell cultures with VEEV to identify the cellular source of IFN-α/β, the timing and extent of translation and/or transcription inhibition in infected cells, and the transcription factors responsible for IFN-α/β induction. In contrast to fibroblast infection, myeloid cell cultures infected with VEEV secreted IFN-α/β that increased until cell death was observed. VEEV inhibited translation in most cells early after infection (<6 h postinfection [p.i.]), while transcription inhibition occurred later (>6 h p.i.). Furthermore, the interferon regulatory factor 7 (IRF7), but not IRF3, transcription factor was critical for IFN-α/β induction in vitro and in sera of mice. We identified a subset of infected Raw 264.7 myeloid cells that resisted VEEV-induced translation inhibition and secreted IFN-α/β despite virus infection. However, in the absence of IFN receptor signaling, the size of this cell population was diminished. These results indicate that IFN-α/β induction in vivo is IRF7 dependent and arises in part from a subset of myeloid cells that are resistant, in an IFN-α/β-dependent manner, to VEEV-induced macromolecular synthesis inhibition.IMPORTANCE Most previous research exploring the interaction of alphaviruses with host cell antiviral responses has been conducted using fibroblast lineage cell lines. Previous studies have led to the discovery of virus-mediated activities that antagonize host cell antiviral defense pathways, such as host cell translation and transcription inhibition and suppression of STAT1 signaling. However, their relevance and impact upon myeloid lineage cell types, which are key responders during the initial stages of alphavirus infection in vivo, have not been well studied. Here, we demonstrate the different abilities of myeloid cells to resist VEEV infection compared to nonmyeloid cell types and begin to elucidate the mechanisms by which host antiviral responses are upregulated in myeloid cells despite the actions of virus-encoded antagonists.

中文翻译：

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髓样细胞对高分子合成物的抗切断能力对感染阿尔法病毒后依赖IRF7的全身性干扰素α/β诱导至关重要。

在体外，成纤维细胞类型的甲病毒感染会抑制宿主细胞的翻译和转录，从而抑制干扰素α/β（IFN-α/β）的产生。但是，感染对髓样细胞的影响尚不清楚，髓样细胞通常是体内甲型病毒首先遇到的细胞。先前的研究表明全身性IFN-α/β的产生与骨髓细胞感染的效率相关。野生型委内瑞拉马脑炎病毒（VEEV）（一种高度髓样细胞嗜性α病毒）对鼠类的感染导致系统中很高水平的IFN-α/β分泌，这表明应答细胞中的应激反应是活跃的。在这里，我们用VEEV感染了骨髓细胞培养物，以鉴定IFN-α/β的细胞来源，感染细胞中翻译和/或转录抑制的时机和程度，以及负责IFN-α/β诱导的转录因子。与成纤维细胞感染相反，用VEEV感染的髓样细胞培养物分泌的IFN-α/β一直增加，直到观察到细胞死亡为止。VEEV在感染后早期（感染后＜6小时）抑制大多数细胞中的翻译，而转录抑制则在感染后（＞ 6小时）发生。此外，干扰素调节因子7（IRF7）而不是IRF3转录因子对于体外和小鼠血清中IFN-α/β的诱导至关重要。我们确定了受感染的Raw 264.7髓样细胞的子集，尽管受到病毒感染，它们仍能抵抗VEEV诱导的翻译抑制并分泌IFN-α/β。然而，在没有IFN受体信号传导的情况下，该细胞群的大小减小了。这些结果表明体内的IFN-α/β诱导是IRF7依赖性的，部分起源于以IFN-α/β依赖性的方式对VEEV诱导的大分子合成抑制有抗性的一部分髓细胞。使用成纤维细胞谱系细胞系进行了先前的研究，探索α病毒与宿主细胞抗病毒反应的相互作用。先前的研究导致发现了病毒介导的活性，该活性可拮抗宿主细胞的抗病毒防御途径，例如宿主细胞的翻译和转录抑制以及STAT1信号的抑制。但是，它们的相关性和对髓系谱系细胞类型的影响尚未得到很好的研究，髓系谱系细胞类型是α病毒体内感染初期的关键应答者。这里，