Xiang Ying, Condit Richard C, Vijaysri Sangeetha, Jacobs Bertram, Williams Bryan R G, Silverman Robert H
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
J Virol. 2002 May;76(10):5251-9. doi: 10.1128/jvi.76.10.5251-5259.2002.
The vaccinia virus E3L gene encodes two double-stranded RNA binding proteins that promote viral growth and pathogenesis through suppression of innate immunity. To explore how E3L enables vaccinia virus to evade the interferon system, cells and mice deficient in the principal interferon-regulated antiviral enzymes, PKR and RNase L, were infected with wild-type vaccinia virus and strains of vaccinia virus from which E3L had been deleted (E3L-deleted strains). While wild-type virus was unaffected by RNase L and PKR, virus lacking E3L replicated only in the deficient cells. Nevertheless, E3L-deleted virus failed to replicate to high titers or to cause significant morbidity or mortality in triply deficient mice lacking RNase L, PKR, and Mx1. To investigate the underlying cause, we determined the effect of E3L on interferon regulatory factor 3 (IRF3), a transcription factor required for viral induction of subtypes of type I interferons. Results showed that IRF3 activation and interferon-beta induction occurred after infections with E3L-deleted virus but not with wild-type virus. These findings demonstrate that E3L plays an essential role in the pathogenesis of vaccinia virus by blocking the interferon system at multiple levels. Furthermore, our results indicate the existence of an interferon-mediated antipoxvirus pathway that operates independently of PKR, Mx1, or the 2-5A/RNase L system.
痘苗病毒E3L基因编码两种双链RNA结合蛋白，它们通过抑制先天免疫来促进病毒生长和发病机制。为了探究E3L如何使痘苗病毒逃避干扰素系统，用野生型痘苗病毒和已缺失E3L的痘苗病毒株（E3L缺失株）感染缺乏主要干扰素调节抗病毒酶PKR和RNase L的细胞和小鼠。虽然野生型病毒不受RNase L和PKR的影响，但缺乏E3L的病毒仅在缺陷细胞中复制。然而，E3L缺失的病毒在缺乏RNase L、PKR和Mx1的三重缺陷小鼠中未能复制到高滴度，也未引起明显的发病率或死亡率。为了探究潜在原因，我们确定了E3L对干扰素调节因子3（IRF3）的影响，IRF3是I型干扰素亚型病毒诱导所需的转录因子。结果表明，感染E3L缺失病毒后会发生IRF3激活和干扰素-β诱导，而感染野生型病毒后则不会。这些发现表明，E3L通过在多个水平阻断干扰素系统在痘苗病毒发病机制中起重要作用。此外，我们的结果表明存在一种独立于PKR、Mx1或2-5A/RNase L系统运行的干扰素介导的抗痘病毒途径。
