A novel innate signalling pathway and its viral antagonism

人类巨细胞病毒（HCMV）感染世界上大多数人，并建立一个持续的，终身感染。虽然大多数人不会患上严重的疾病，但免疫功能低下的个体，如移植受者，可能会患上毁灭性的疾病，包括器官排斥、多器官衰竭甚至死亡。此外，未出生的婴儿感染丙型巨细胞病毒的风险特别大，无论是在怀孕期间感染丙型巨细胞病毒的母亲还是已经感染丙型巨细胞病毒的母亲。总体而言，约有1/100的妊娠受到影响，HCMV是导致儿童耳聋和智力残疾的主要感染原因，也是导致出生缺陷的最重要病毒原因之一。抵抗HCMV和其他病毒的第一道防线之一是特定的“感应蛋白”，它可以检测感染并激活“信号蛋白”来触发关键的免疫反应。为了能够复制，一些病毒如HCMV已经发展出破坏这些蛋白质的机制。我们的目标是了解我们的细胞如何通过表征以前未发现的信号蛋白来检测HCMV和其他病原体。我开发了新的技术来识别信号蛋白，根据它们如何在细胞内移动来警告感染，以及它们是否被病毒破坏。在最初的实验中，我们发现了两种新的病毒信号蛋白。至关重要的是，这些蛋白不仅会被HCMV感染激活，还会被一种进化上不同的病毒——仙台病毒（Sendai）激活。这暗示了对病毒感染的一般反应，并且可能是对不同类型病原体感染的一般反应。有趣的是，一种蛋白质触发抗病毒分子的产生，可以抑制HCMV，并在感染后迅速被病毒破坏，而另一种蛋白质则促进感染——病毒甚至使用自己的一种蛋白质来辅助这一过程。我们现在希望更详细地了解这些蛋白质是如何工作的，特别是它们是如何被传感蛋白激活的，它们究竟产生了哪些抗病毒或前病毒分子，以及它们是如何调节和被HCMV和其他病毒破坏的。为了实现这些目标，我们将研究皮肤细胞和免疫传感细胞，它们在HCMV感染中都发挥着重要而独特的作用。在本实验室均可感染HCMV和仙台病毒。通过了解HCMV和其他病毒如何破坏信号蛋白，我们最终将能够开发出重要的新疗法来预防由病毒感染引起的疾病。至关重要的是，这些知识也将极大地提高我们对病毒免疫力的理解。

Human cytomegalovirus (HCMV) infects most people worldwide, and establishes a persistent, lifelong infection. Although most people do not suffer from serious illness, immunocompromised individuals such as transplant recipients can suffer from devastating disease including organ rejection, multi-organ failure and even death. Furthermore, unborn babies are at a particular risk from HCMV, both in mothers who become infected during pregnancy and in mothers who already have the virus. Overall ~1/100 pregnancies are affected, and HCMV is the leading infectious cause of deafness and intellectual disability in children, and one of the most significant viral causes of birth defects.One of the first lines of defence against HCMV and other viruses are specific 'sensing proteins', which can detect infection and activate 'signalling proteins' to trigger critical immune responses. To be able to replicate, some viruses such as HCMV have developed mechanisms to subvert these proteins.Our aim is to understand how our cells detect HCMV and other pathogens by characterising previously undiscovered signalling proteins. I have developed new technologies to identify signalling proteins based on how they move within cells to warn of infection, and whether they are destroyed by viruses.In initial experiments, we have discovered two novel viral signalling proteins. Crucially, these proteins are activated not only by infection with HCMV but also infection with an evolutionally distinct virus - Sendai. This is suggestive of a general response to viral infection, and potentially a general response to infection by diverse types of pathogen. Intriguingly, whereas one protein triggers the production of antiviral molecules that can inhibit HCMV, and is rapidly destroyed by the virus upon infection, the other acts to promote infection - and the virus even uses one of its own proteins to assist this process. We now wish to understand how these proteins work in much more detail, specifically how they are activated by sensing proteins, exactly which antiviral or proviral molecules they cause to be produced, and how they regulate and are subverted by HCMV and other viruses. To achieve these aims, we will study skin cells and immune sensing cells, which both play vital yet distinct roles in HCMV infection. Both can be infected with HCMV and Sendai virus in our laboratory.By understanding how HCMV and other viruses subvert signalling proteins, we will ultimately be able to develop vital new treatments to prevent diseases caused by viral infection. Crucially, this knowledge will also dramatically improve our understanding of immunity to viruses in general.