Self RNA sensing by cytosolic innate immune receptors

免疫系统是一个复杂的网络，可以保护人体免受包括病毒在内的感染。这一庞大而多样的微生物群导致从普通感冒到艾滋病和COVID-19等疾病，病毒继续构成大流行暴发的风险。免疫系统可以消灭病毒，因此了解免疫反应是如何在感染时启动的是很重要的。第一步是我们体内的细胞识别病毒的存在。我们知道细胞有专门的蛋白质，叫做传感器，用来检测病毒。然而，这些天线如何感知病毒尚不完全清楚。所有病毒的一个特性是它们以DNA或RNA的形式将遗传物质引入它们感染的细胞中。这些外来核酸分子可以激活一些病毒传感器，然后引发第一波免疫反应，即先天免疫。令人惊讶的是，我们的初步数据表明，细胞产生的自身RNA分子也可以激活先天免疫系统。我们发现内含子，一种通常在细胞核中迅速降解的RNA，在病毒感染细胞的细胞质中积累，并与一种称为MDA5的传感器结合。从概念上讲，我们提出MDA5通过检测病毒诱导的扰动而不是病毒直接引入的分子来保护细胞免受感染。我们的第一个目标是通过应用分子生物学研究来鉴定不同病毒感染期间MDA5结合的rna，为这一概念提供证据。这将包括重要的人类病毒，如SARS冠状病毒、丙型肝炎病毒和单纯疱疹病毒。另一个重要的RNA传感器是ZBP1蛋白。与我们在MDA5中发现的类似，我们未发表的结果表明，ZBP1结合线粒体RNA，这种细胞RNA通常只存在于线粒体中，而线粒体是一种缺乏ZBP1的亚细胞器。因此，我们的第二个目标是研究细胞应激损害线粒体的想法，导致线粒体RNA逃逸到细胞的细胞质中，在那里它可能被ZBP1检测到，采用一种不寻常的构象称为“Z”。这项工作将采用已经用于MDA5的类似RNA结合技术。细胞在一个被称为RNA编辑的过程中不断地修改自己的一些RNA，腺苷被转化为肌苷，改变RNA的生化特性。先前对人类遗传疾病和体内模型的研究表明，在没有感染的情况下，RNA编辑可以防止对自身RNA的不必要的先天免疫反应。然而，当RNA编辑因突变而失效时，MDA5和ZBP1变得活跃，从而释放出严重的炎症和自身免疫性疾病。一个重要的知识缺口是，需要编辑以预防疾病的rna类型仍然缺乏特征。我们的假设是Z构象的rna很重要。我们将识别这些z - rna以及它们引发不必要免疫反应的组织和细胞类型。这项工作将利用体内模型和来自自身炎症性疾病患者的细胞，其中一种名为ADAR1的蛋白质（可以编辑RNA）不能与Z-RNA结合。我们预计，我们的工作将建立细胞质自身RNA传感，除了检测外源RNA，作为免疫监测和体内平衡的主要模式。这将是对这一研究领域认识的重大转变，并将为许多疾病的新治疗方法的发展提供信息。激活胞质RNA受体可增强病毒感染的免疫反应。此外，该策略可与检查点阻断等癌症治疗协同使用，从而激活免疫系统的适应性臂。反之亦然，阻断RNA传感器可能对许多非传染性疾病和从代谢紊乱到衰老等都涉及炎症的病症有益。

The immune system is a complex network that protects the human body against infections, including with viruses. This large and diverse group of microorganisms causes diseases ranging from the common cold to AIDS and COVID-19, and viruses continue to pose the risk of pandemic outbreaks. The immune system can eliminate viruses, and it is therefore important to understand how the immune response is kick-started upon infection. The first step is that the cells in our body recognise the presence of a virus. We know that cells have specialised proteins called sensors that detect viruses. However, how these antennas sense viruses is not fully understood. One property of all viruses is that they introduce genetic material in the form of DNA or RNA into the cells that they infect. These foreign nucleic acid molecules can activate some virus sensors that then induce a first wave of immune responses called innate immunity.Surprisingly, our preliminary data indicate that self RNA molecules produced by cells can also activate the innate immune system. We found that introns, a type of RNA normally degraded quickly in the nucleus of cells, accumulate in the cytoplasm of virus-infected cells, and bind to a sensor called MDA5. Conceptually, we propose that MDA5 guards cells against infection by detecting virus-induced perturbations rather than molecules directly introduced by the virus. Our first aim is to provide evidence for this concept by applying molecular biology studies to identify the RNAs bound by MDA5 during different viral infections. This will include important human viruses such as SARS coronavirus 2, hepatitis C virus and herpes simplex virus 1.Another important RNA sensor is the ZBP1 protein. Akin to what we found for MDA5, our unpublished results show that ZBP1 binds mitochondrial RNA, a cellular RNA that is normally found only in mitochondria, a sub-cellular organelle devoid of ZBP1. Our second aim is therefore to investigate the idea that cellular stress damages mitochondria, resulting in escape of mitochondrial RNA into the cytosol of cells, where it may be detected by ZBP1 upon adopting an unusual conformation called 'Z'. This work will employ similar RNA binding techniques already used for MDA5.Cells continuously modify some of their own RNAs in a process called RNA editing, whereby adenosine is converted to inosine, changing the biochemical properties of the RNA. Previous studies of human genetic disease and in vivo models revealed that RNA editing, in the absence of infections, prevents unwanted innate immune responses to self RNA. However, when RNA editing is disabled due to mutations, MDA5 and ZBP1 become active and profound inflammation and autoimmune disease are unleashed. An important knowledge gap is that the types of RNAs that need to be edited to prevent disease remain poorly characterised. Our hypothesis is that RNAs in the Z conformation are important. We will identify such Z-RNAs and the tissues and cell types in which they trigger unwanted immune responses. This work will take advantage of an in vivo model and of cells from patients with autoinflammatory disease in which a protein called ADAR1, which edits RNA, cannot bind to Z-RNA.We anticipate that our work will establish cytosolic self RNA sensing, in addition to detection of foreign RNA, as a predominant mode of immune surveillance and homeostasis. This will be a significant shift of understanding in this area of research and will inform the development of new treatments for many diseases. Activation of cytosolic RNA receptors may boost immune responses in viral infections. Moreover, this strategy may be used in synergy with cancer treatments such as check-point blockade, which activate the adaptive arm of the immune system. Vice versa, blocking RNA sensors may be beneficial in many non-infectious diseases and conditions ranging from metabolic disorders to ageing that all involve inflammation.