VIRAL IMMUNE EVASION RESEARCH
Our major research interest is understanding how the innate immune system senses viruses and subsequently signals altered gene expression. The innate immune system responds to viruses using several classes of germline-encoded pattern recognition receptors (PRRs) to recognise pathogen-associated molecular patterns (PAMPs), and trigger anti-viral signalling pathways. This leads to the induction of interferons (IFNs) and cytokines, which control infection locally as well as coordinating the adaptive immune response. PRRs, such as the Toll-like receptors (TLRs), RIG-like receptors (RLRs) and cytosolic DNA sensors are important not only for responses to pathogens but also in sepsis, sterile inflammation, and autoimmune diseases. Current specific projects include:
1. Innate immune intracellular DNA sensing by ‘ALRs'
It has been known for some time that microbial DNA in the cytosol is immune-stimulatory, leading to IFN-beta induction, but the PRRs responsible for this response have remained elusive. We recently identified a novel cytosolic DNA sensor called IFI16, which is a PYRIN and HIN domain-containing (PYHIN) protein. IFI16 directly associated with IFN- beta -inducing viral DNA motifs in the cytosol, while siRNA targeting IFI16 or the mouse PYHIN protein p204 inhibited gene induction and activation of IRF3 and NF kappa B induced by transfected DNA or a DNA virus. Another PYHIN protein, AIM2, had been shown to be mediate DNA-induced activation of the inflammasome. Thus, we have proposed that the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors termed ‘AIM2-like receptors' (ALRs).
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. Poxviruses such as VACV have large dsDNA genomes, which contain open reading frames (ORFs) that encode numerous proteins shown to be involved in antagonising the host immune response. Therefore VACV represents a powerful 'toolbox' with which to probe the molecular mechanisms of immunity. All viruses need to suppress the type I IFN response in order to successfully become established in a host, and using functional screens we have identified novel VACV IFN inhibitors that target PRR pathways. By identifying and characterising the host targets of these viral inhibitors, we are hoping to more fully understand the human anti-viral response.
3. Characterising the role of mammalian SARM
Four TLR adapter proteins have been shown to be essential for transducing the signal of various TLRs, for example TRIF has a role in the TLR3 and TLR4 pathways. We previously showed that the fifth member of the adapter family, SARM (Sterile alpha and HEAT/Arm motif containing protein), negatively regulates TRIF function in human cells. SARM is highly conserved across different organisms, from worms to humans, and thus mammalian SARM likely has further yet to be discovered functions.
4. The role of human IRAK-2 in TLR signalling
The particular role of IL-1 receptor-associated kinase-2 (IRAK-2), and whether it is redundant with IRAK-1, has remained unclear. Recently we have shown that IRAK-2 has a fundamental role in TLR signalling pathways leading to NFkappaB activation. Ongoing studies are seeking to address the various potential transcriptional and post-transcriptional roles of IRAK-2 in primary human cells.
Lab manager (part-time):
Science Foundation Ireland
Jose Bengoechea, Queens University Belfast.
Recent Publications by Andrew Bowie and the Viral Immune Evasion group
Last updated: Jan 14 2014.