Professor Andrew Bowie
Viral Immune Evasion
Professor Andrew Bowie
Location: Room 4.24, Trinity Biomedical Sciences Institute
View audio/video clip of Prof Bowie talking about his research (mp4, 47.6MB)
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. Some current projects are listed below:
1. Role of PYHIN proteins in innate immunity
It has been known for some time that microbial DNA in the cytosol is immune-stimulatory, leading to IFN-beta induction, and we identified a novel cytosolic DNA sensor called IFI16, which is a PYRIN and HIN domain-containing (PYHIN) protein that mediate IFN-beta induction by cytosolic DNA. 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). Human have five PYHIN proteins (IFI16, AIM2, POP3, PYHIN1, MNDA), and mice have many more. Apart from roles in DNA sensing, PYHIN proteins also regulate transcription of specific cytokines and IFNs induced by PRRs.
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 vaccinia virus (VACV) and molluscum contagiosum virus (MCV) have large dsDNA genomes, which contain open reading frames (ORFs) that encode proteins shown to be involved in antagonising the host immune response. Therefore VACV and MCV represent powerful 'toolboxes' 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 and MCV inhibitors of 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. The fifth member of the adapter family, SARM (Sterile alpha and HEAT/Arm motif containing protein), is highly conserved across different organisms, from worms to humans. We have shown that mammalian SARM negatively regulates TRIF function in human cells. SARM also has TLR-independent roles, such as in CCL5 induction in macrophages, and also in regulating cell death in neuronal cells.
Marcin Baran, PhD
Gareth Brady, PhD
Michael Carty, PhD
Dympna Connolly, PhD
Sinead Flannery, PhD
David Casserly, BA (Mod)
Alan Dempsey, BA (Mod)
Jay Kearney, BA (Mod)
Mariann Landsberger, MSc
Davide Massa, MSc
Jana Musilova, MSc
Lab manager (part-time):
Laura Madrigal-Estebas, PhD
Science Foundation Ireland
National Institutes of Health (NIH)
European Union Seventh Framework Programme
The Health Research Board (HRB)
Jose Bengoechea, Queens University Belfast.
Kate Fitzgerald, University of Massachusetts Medical School.
Pavel Kovarik, Max F Perutz Laoratories, Austria.
Soren Paludan, University of Aarhus.
Andreas Pichlmair, Max-Planck Institute for Biochemistry, Munich.
Alex Weber, University of Tübingen.
T. Sam Xiao, Laboratory of Immunology, NIH.
We are part of the EU-funded Infection Biology Training Network (INBIONET) – see www.inbionet.eu for information on research goals, news and blogs.