Harte Mary T, Haga Ismar R, Maloney Geraldine, Gray Pearl, Reading Patrick C, Bartlett Nathan W, Smith Geoffrey L, Bowie Andrew, O'Neill Luke A J
The Cytokine Research Group, Department of Biochemistry, Trinity College, Dublin 2, Ireland.
J Exp Med. 2003 Feb 3;197(3):343-51. doi: 10.1084/jem.20021652.
Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor kappa B (NF-kappa B) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor-associated kinase 2 (IRAK2) and tumor necrosis factor receptor-associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response.
Toll样受体（TLRs）在对病原体的固有免疫反应中至关重要，因为它们识别并响应病原体相关分子模式，从而导致细胞内信号通路的激活和基因表达的改变。牛痘病毒（VV），即用于预防天花的痘病毒，编码可拮抗宿主抗病毒防御重要成分的蛋白质。在此我们表明，VV蛋白A52R可阻断包括TLR3（一种最近鉴定出的病毒RNA受体）在内的多种TLR对转录因子核因子κB（NF-κB）的激活。A52R与白细胞介素1受体相关激酶2（IRAK2）和肿瘤坏死因子受体相关因子6（TRAF6）均相关联，这两种蛋白是TLR信号转导中的关键蛋白。此外，A52R可破坏含有这些蛋白的信号复合物。在小鼠鼻内感染模型中，与野生型和回复突变对照相比，缺乏A52R基因的病毒缺失突变体的毒力减弱。本研究揭示了VV用于抑制宿主免疫的一种新机制。我们证明了病毒对TLR的抑制作用，为该受体家族在抗病毒反应中的重要作用提供了进一步证据。
