Self RNA sensing by cytosolic innate immune receptors

胞质先天免疫受体的自身 RNA 传感

• 批准号: MR/Y013212/1
• 负责人: Jan Rehwinkel
• 金额: $ 225.88万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013212%2F1
• 关键词: Self; RNA; sensing; cytosolic; innate

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 Akin to what we found for MDA5, our unpublished results show that ZBP1 binds mitochondrial RNA, a cellular RNA that is normally found only in mitochondria, a sub-cellular organelle devoid of ZBP1.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.

免疫系统是一个复杂的网络，它保护人体免受感染，包括病毒感染。这一庞大而多样的微生物群会导致从普通感冒到艾滋病和新冠肺炎的各种疾病，病毒继续构成大流行爆发的风险。免疫系统可以清除病毒，因此了解感染后免疫反应是如何启动的是很重要的。第一步是我们体内的细胞识别病毒的存在。我们知道，细胞有一种特殊的蛋白质，称为传感器，可以检测病毒。然而，这些天线是如何感知病毒的还没有完全弄清楚。所有病毒的一个特点是它们将DNA或RNA形式的遗传物质引入它们感染的细胞中。这些外来的核酸分子可以激活一些病毒感应器，然后诱导第一波称为先天免疫的免疫反应。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，内含子是一种通常在细胞核中迅速降解的RNA，它会在感染病毒的细胞的细胞质中积累，并与一种名为MDA5的传感器结合。从概念上讲，我们认为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识别不同病毒感染过程中MDA5结合的RNA，从而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2，丙型肝炎病毒和单纯疱疹病毒1。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与线粒体RNA结合，线粒体RNA是一种通常只在线粒体中发现的细胞RNA，线粒体是一种缺乏ZBP1的亚细胞细胞器。因此，我们的第二个目标是研究细胞应激损伤线粒体，导致线粒体RNA逃逸到细胞胞浆中，在那里ZBP1可能会检测到采用了一种称为“Z”的不寻常构象。这项工作将采用已经用于MDA5的类似的RNA结合技术。细胞在一个称为RNA编辑的过程中不断修改自己的一些RNA，通过这个过程，腺苷被转化为肌苷，改变RNA的生化性质。之前对人类遗传病和活体模型的研究表明，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编辑由于突变而被禁用时，MDA5和ZBP1会变得活跃，并引发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类型仍然没有得到很好的描述。我们的假设是，Z构象中的RNA是重要的。我们将确定这样的Z-RNA以及它们触发不必要的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，在这种情况下，一种名为ADAR1的蛋白质编辑RNA，不能与Z-RNA结合。我们预计，除了检测外源RNA外，我们的工作还将建立细胞质自我RNA检测，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开发提供信息。胞质RNA受体的激活可能会增强病毒感染的免疫反应。此外，这一策略可以与癌症治疗协同使用，例如检查点封锁，它激活了免疫系统的适应性手臂。反之亦然，阻断RNA感受器在许多非传染性疾病和从代谢紊乱到衰老的各种情况下都涉及炎症可能是有益的。