Rehwinkel Group: Nucleic Acid Sensing
Nucleic acids are triggers for many innate immune responses. This is best understood in the context of virus infection. When viruses infect cells, their nucleic acids – such as viral DNA and RNA genomes, replication intermediates or viral transcripts – are detected by germ-line encoded receptors. These sensors of virus invasion then engage different signalling pathways to induce an antiviral state. This includes the production of interferons and other cytokines, stress responses and programmed cell death. Viruses cannot replicate and complete their life cycles without introducing their RNA or DNA genomes into host cells. Nucleic acid sensing is therefore a broadly effective cellular defence strategy for the detection of virus infection. However, the presence of vast quantities of cellular RNAs and DNAs in healthy, uninfected cells necessitates molecular mechanisms of self / non-self discrimination and poses the risk of unwanted immune responses in the absence of infection. Indeed, nucleic acid sensing pathways have been linked to autoinflammatory and autoimmune diseases. Moreover, nucleic acids are also involved in priming immune responses targeting cancers and are potent adjuvants for vaccination. The study of nucleic acid sensing is thus important to our understanding of host-pathogen interactions and the aetiology of some autoimmune diseases, and is likely to inform the development of novel therapies.
Our research focuses on the molecular biology of activation and regulation of innate immune receptors that survey the cytosol. We use a variety of virus infection models including influenza A virus, HIV and other retroviruses, flaviviruses such as Zika virus, SARS-CoV-2 and herpesviruses. In addition, we are studying the role of nucleic acid sensing in inflammatory diseases and in cancer. We are particularly interested in RIG-I-like receptors and cytosolic DNA receptors such as cGAS. Furthermore, we are interested in SAMHD1 and ADAR1, which restrict virus infection and are also linked to Aicardi-Goutières syndrome – an autoinflammatory disease driven by interferons.
RIG-I is a cytosolic sensor that detects infection with RNA viruses and recognizes RNA. In the past, we identified the RNAs detected by RIG-I in infected cells as viral RNA genomes bearing 5’-triphosphates (Rehwinkel et al., Cell 2010). These results provide an explanation for the selective triggering of RIG-I in infected cells as most cytosolic cellular RNAs lack 5’-triphosphate groups.
As with RNA, DNA also induces an antiviral interferon response if it accumulates in the cytosol of cells during virus infection. Cellular proteins called DNA sensors detect cytosolic DNA. One of these proteins is cGAS that signals for the induction of innate immune responses via production of a second messenger, cGAMP. We discovered that cGAMP is incorporated into enveloped virus particles when these bud from an infected cell (Bridgeman et al., Science 2015). Fusion of cGAMP-loaded virus particles with target cells delivers cGAMP into those cells, resulting in the rapid induction of interferon. These observations suggest that infected cells exploit virus particles as “Trojan Horses” to disseminate a signal for innate immunity. In addition, this finding has translational implications for the design of vaccines and for the use of oncolytic viruses.
We believe that engaging the public with the research that we do is an important part of our work. We do this through a combination of online and face-to-face engagement activities. Former DPhil students Antonio Gregorio Dias Jr and Layal Liverpool regularly wrote science articles targeted at non-expert adults, including for the WIMM blog and the Science Innovation Union (SIU) Oxford branch (eg this article about Zika virus). In this short podcast, group leader Jan Rehwinkel explains in simple terms how the innate immune system detects flu virus. Layal Liverpool also frequently gave talks themed around her DPhil research to non-expert audiences and, in 2016, her short talks on HIV and flu landed her in the regional final of the science communication competition FameLab UK. Lab members additionally participate in broader public engagement activities through the department, for example by communicating research from the institute to the general public as part of the annual MRC Festival.