Enemy at the gate: a novel mechanism of paracrine stress granule induction by viruses

体内的细胞以多种方式对外界刺激作出反应，其中最常见的是通过调节基因表达。为了应对诸如感染之类的压力，细胞可以暂停蛋白质合成或翻译，从而通过将信使rna （mrna）储存在称为压力颗粒的细胞室中来暂停遗传信息的解码。这种防御机制允许细胞通过限制蛋白质合成所需的能量和营养物质的使用来生存，直到压力得到解决。它还可以阻止病毒的传播，因为它们依赖宿主细胞资源来产生病毒蛋白并进行复制。因为压力颗粒也作为哨兵来感知病毒的攻击，病毒已经开发出了使其功能失效的策略。压力颗粒也越来越重要，因为最近的观察表明，它们与神经退行性疾病，如肌萎缩侧索硬化症和阿尔茨海默病，以及对癌症化疗的耐药性有关。杯状病毒是一种重要的小病毒家族，可引起人类和动物疾病。在人类中，它们主要引起肠胃炎，但在动物中也引起全身感染和呼吸道感染。利用动物杯状病毒，我们以前在确定病毒用来操纵宿主细胞和抵消细胞防御系统的新机制方面取得了重大进展。基于我们最近的研究结果，我们现在提出，在对病毒感染的反应中，一种新机制允许未感染的细胞激活应激反应并为病毒攻击做好准备。这种机制是新颖的，我们认为它代表了对抗病毒的新防线。因此，我们的目标是结合使用细胞生物学、病毒学和生化方法来表征在感染反应中组装的应激颗粒的组成；了解它们在2-蛋白质合成的重塑和3-抗病毒反应中的作用，以及4-确定哪些可溶性分子刺激了这一机制。通过这项工作，我们期望充分了解病毒如何调节应激颗粒的组装，并启动抗病毒状态。然后我们就能找到抑制病毒复制的新方法。因此，我们的工作将描述抗病毒反应的新机制。它将推进我们对应激颗粒如何控制基因表达的基本知识，并有助于开发针对这一重要病毒组的新型抗病毒疗法，以及后来控制应激途径的其他病毒。

Cells within the body respond to external stimuli in many ways, the most common of which is via the regulation of gene expression. In response to stress such as infection, cells can pause protein synthesis, or translation, and thus the decoding of genetic information, by storing messenger RNAs (mRNAs) away in cellular compartments called stress granules. This defence mechanism allows cells to survive by limiting the use of energy and nutrients that protein synthesis requires until the stress is resolved. It also blocks the spread of viruses as they are dependent on host cell resources to produce viral proteins and replicate. Because stress granules also act as sentinels to sense viral attack, viruses have developed strategies to disable their function. Stress granules are also of increasing importance because of recent observations that they are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as resistance to cancer chemotherapy.Caliciviruses are an important family of small viruses that can cause diseases both in humans and animals. In humans they primarily cause gastroenteritis but also cause general and respiratory infections in animals. Using animal caliciviruses, we previously made significant advances in identifying new mechanisms that viruses use to manipulate the host cell and counteract the cell's defence systems. Based on our recent results, we are now proposing that in response to virus infection, a novel mechanism allows uninfected cells to activate stress responses and prepare for viral assault. This mechanism is novel and we think it represents a new line of defence against viruses. Therefore, our objectives are to use a combination of cell biology, virology and biochemical methods to 1- characterise the composition of stress granules assembled in response to infection; understand their role in 2- the remodelling of protein synthesis and 3- the antiviral response, and 4- identify which soluble molecules stimulate this mechanism.From this work we expect to fully understand how viruses regulate the assembly of stress granules, and prime an antiviral state. We can then identify new ways to inhibit virus replication. Therefore, our work will characterise a new mechanism of antiviral response. It will advance our basic knowledge of how stress granules control gene expression and aid in the development of novel antiviral therapies for this important group of viruses, and later other viruses that control stress pathways.