Regulation of the dsDNA sensor protein-mediated anti-viral response by vaccinia virus

当我们的身体被病毒或细菌感染时，敏感的检测系统会感应到感染微生物，从而激活并协调对感染的免疫反应。宿主的即时反应称为先天反应。这对于帮助快速限制微生物的传播至关重要，但对于激活免疫反应的第二个方面（获得性免疫）也非常重要，免疫反应包括识别并摧毁微生物或被其感染的细胞的特异性抗体和T细胞。了解细胞识别入侵微生物的分子机制对于开发治疗方法以帮助控制由这些危险微生物（病原体）引起的疾病非常重要。病毒只能在细胞内复制，因此在进化过程中，我们已经开发出可以检测细胞内病毒核酸（DNA或RNA）的系统。细胞蛋白识别RNA已经有一段时间了，但外源DNA的传感器最近才被报道（2007年）。有趣的是，发现的DNA传感器（称为DAI）与牛痘病毒（一种痘病毒，用于根除天花的疫苗）中的蛋白质（E3）有相似之处。E3蛋白仅在前半部分与DAI相似，已知E3的这一部分与DNA结合并使病毒更危险（毒性），但机制未知。像VACV这样的痘病毒含有许多阻断宿主对感染反应的蛋白质，E3就是其中一个例子。该项目将确定E3蛋白是否如我们所建议的那样能够阻断DAI的作用，从而阻止我们的细胞对痘病毒感染的有效反应。这一信息对于增进我们对免疫系统以及病毒如何阻断免疫系统的理解非常重要，但也将在设计和构建VACV和其他痘病毒毒株方面具有实际应用价值，这些毒株是治疗传染病和癌症的更好的疫苗。

When our body is infected by viruses or bacteria the infecting microbes are sensed by sensitive detection systems that can activate and co-ordinate an immune response to the infection. The immediate response by the host is called the innate response. This is crucial for helping to restrict spread of the microbe quickly, but is also very important for the activation of the second aspect of the immune response (acquired immunity) that comprises specific antibodies and T cells that recognise and destroy the microbe or cells infected by it. Understanding the molecular mechanisms by which our cells recognise invading microbes is very important in the development of therapies to help control disease caused by these dangerous microbes (pathogens). Viruses can replicate only inside cells and so during evolution we have developed systems that can detect virus nucleic acid (DNA or RNA) within our cells. Cellular proteins that recognise RNA have been known for some time but a sensor for foreign DNA was only reported recently (2007). Intriguingly, the DNA sensor discovered (called DAI) shares similarity to a protein (E3) from vaccinia virus (VACV) (a poxvirus, and the vaccine used to eradicate smallpox). The E3 protein is similar to DAI only in its first half and this part of E3 is known to bind DNA and make the virus more dangerous (virulent), but by an unknown mechanism. Poxviruses such as VACV contain many proteins that block the host response to infection, and E3 is one example of these. This project will determine if, as we propose, the E3 protein functions to block the action of DAI and thereby stop our cells responding efficiently to infection by poxviruses. This information will be important in increasing our understanding of the immune system and how viruses block this, but will also have practical application in the design and construction of strains of VACV and other poxviruses that are better vaccines to treat infectious diseases and cancer.