About our research interests
The innate immune system senses both danger (e.g. tissue damage) and stranger (e.g. viruses) through pattern recognition receptors (PRRs) and inflammasome complexes, leading to production of cytokines and interferons (IFNs) that mobilise an appropriate immune response. However, when these responses are dysregulated, autoimmune and inflammatory disease ensues.
Our research focuses on innate immune sensing and signalling mechanisms, and their modulation by viruses. We are examining how viruses and other pathogens are initially detected by the innate immune system, leading to the activation of transcription factors and altered gene expression. We also investigate how viruses evade and subvert detection by the host immune response. This work has shed light on how PRRs such as Toll-like receptors (TLRs) and cytosolic DNA sensors recognise pathogens, leading to the induction of IFNs and pro-inflammatory cytokines. These IFNs and cytokines control infection locally as well as coordinating the adaptive immune response. We also investigate how PRRs and inflammasomes drive inflammation through the recognition of nucleic acid such as mislocalised self-DNA, to more fully understand how autoimmune and inflammatory diseases are initiated and exacerbated. Through these studies, we have identified novel regulators of IFN and cytokine induction, which may be candidate drug targets or biomarkers in autoimmune and inflammatory disease. Some current projects are listed below:
1. Role of PYHIN proteins in innate immunity
Microbial DNA in the cytosol is immune-stimulatory, and we identified a cytosolic DNA sensor called IFI16, which is a PYRIN and HIN domain-containing (PYHIN) protein that mediates IFNbeta induction by cytosolic DNA. Another PYHIN protein, AIM2, mediates DNA-induced activation of the inflammasome. Humans have five PYHIN proteins (IFI16, AIM2, POP3, PYHIN1, MNDA), and mice have many more. Aberrant expression of PYHINs is linked to some autoimmune and inflammatory diseases. Apart from roles in DNA and viral sensing, PYHIN proteins also regulate transcription of specific cytokines and IFNs induced by PRRs, and also directly restrict both DNA and RNA viruses. We are examining the role of PYHINs in human disease and in viral sensing, and also determining the mechanisms whereby PYHINs regulate gene expression.
2. Viral evasion of PRR signalling
Studying the mechanisms whereby viruses evade and subvert the host immune system has yielded valuable insights as to how the host immune machinery functions. All viruses need to suppress the type I IFN response in order to successfully become established in a host. By identifying and characterising such virally-encoded inhibitors, and their host targets, we are gaining a more complete picture of the viral-host interface, which has relevance to both anti-viral immunity and viral pathogenesis.
3. Role of nucleic acid sensing in innate immune detection of respiratory viruses
The ability of human cells to sense the presence of non-self or mis-localised host nucleic acid is a fundamental aspect of our innate immune response to pathogens. Nucleic acid (NA) sensing is particularly important in understanding how innate immune detection of respiratory viruses in lung epithelial cells operates, leading to the initial mobilisation of the anti-viral immune response. Although pattern recognition receptors and inflammasomes that sense viral NA have been identified, especially in myeloid cells, we still know surprisingly little about how the NA sensing machinery operates in the initial detection of respiratory viruses in the human lung. We are examining the shared and distinct NA sensing mechanisms employed in detecting the respiratory viruses influenza A virus (IAV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung epithelial cells, in order to improve our understanding of how exactly NA sensing is involved in the initial detection of three respiratory viruses that are a major burden to human health.