Nucleic Acid Sensing by Innate Immune Receptors

We are trying to work out how the immune system is activated in virus infection and inflammatory disease. Cells infected by virus respond by producing anti-viral factors, which block viral replication and help to control infection. We are interested in a cell molecule called RIG-I, which detects infection with viruses such as influenza A virus. RIG-I recognizes the presence of viral genomes made of RNA. However, normal cells also contain RNA as this is the ‘messenger’ molecule that allows the DNA genes of cells to be copied and translated into protein. How, then, can RIG-I distinguish between the RNA of the cell and the RNA of the virus? The answer lies in a structure called a ‘cap’ found at the starting point of cellular RNAs. Viral RNA genomes do not have this ‘cap’ and RIG-I specifically responds only to RNAs lacking this structure. This is why only cells infected by viruses produce anti-viral factors. By working out how RIG-I and other receptors detect infection with a variety of viruses we aim to understand how this type of immune response is controlled. In a second line of research, we are interested in inflammatory diseases such as Aicardi-Goutieres syndrome that result of the anti-viral pathways being triggered aberrantly in the absence of infection. We hope to determine how deregulation of these pathways can result in disease and find ways of controlling inappropriate inflammatory responses.

The innate immune response is critical for successful host defence against virus infection. Cell-intrinsic mechanisms detect virus presence and signal for the induction of innate response genes such a type I interferons (IFNs) (1). Nucleic acids are often a molecular signature of virus infection and are recognised by innate receptors such as toll-like receptors and RIG-I-like receptors. In addition to their protective role in infectious disease, some of these receptors have also been implicated in inflammatory conditions. Research in my group dissects the molecular biology of activation and regulation of the innate immune receptors that sense nucleic acids both in virus infections and in inflammatory disease. Previously, we showed that progeny viral RNA genomes are recognized by RIG-I in cells infected with negative strand RNA viruses such as influenza A virus (2). These genomes bear a triphosphate moiety on the 5’-end that is essential for RIG-I activation and IFN induction (2). Such 5’-PPP-groups are absent from cellular RNA in the cytoplasm, providing an explanation for the specific triggering of RIG-I in virus-infected cells. We also contributed to projects studying the role of MDA5 and PKR in the immune response to viral infection and the induction of interferon (3,4). Currently, we are working on three complementary aspects of the sensing of nucleic acids by innate immune receptors. Firstly, by using clinically relevant viruses such as picornaviruses and hepatitis C virus, we will characterize the types of RNA recognized by RIG-I and the related receptors MDA5 and LGP2, and the mechanisms of activation of these receptors, in infected cells. Secondly, to determine how the strength and duration of the innate immune responses is controlled we will dissect the mechanisms regulating the expression of pattern recognition receptors and downstream signalling molecules at the post-transcriptional level. Thirdly, because aberrant activation of innate nucleic acid sensing pathways can lead to inflammatory diseases through the triggering of intracellular DNA and RNA sensors and the induction of type I IFN, we are studying the molecular basis of Aicardi-Goutieres syndrome. This genetic disorder mimics virus infection and is characterized by spontaneous IFN production (5). Taken together, this work at the intersection of molecular biology and immunology will provide important insights into activation of the innate immune system by nucleic acids. Our findings will have major implications for virus infection, inflammatory and autoimmune diseases and the development of vaccine adjuvants. References: (1) Rehwinkel and Reis e Sousa 2010 Science 327: 284; (2) Rehwinkel et al 2010 Cell 140: 397; (3) Schulz et al 2010 Cell Host Microbe 7:354; (4) Pichlmair et al 2009 J Virol 83: 10761; (5) Crow and Rehwinkel 2009 Hum Mol Genet 18:R130