Self RNA sensing by cytosolic innate immune receptors

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 Akin to what we found for MDA5, our unpublished results show that ZBP1 binds mitochondrial RNA, a cellular RNA that is normally found only in mitochondria, a sub-cellular organelle devoid of ZBP1.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