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Professor Andrew Bowie

Viral Immune Evasion


Professor Andrew Bowie
Phone: +353-1-8962435
Fax: +353-1-6772400
Email: agbowie@tcd.ie
Location: Room 4.24, Trinity Biomedical Sciences Institute


RESEARCH INTERESTS


View audio/video clip of Prof Bowie talking about his research (mp4, 47.6MB)

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
It has been known for some time that microbial DNA in the cytosol is immune-stimulatory, leading to type I IFN induction, and we identified a novel cytosolic DNA sensor called IFI16, which is a PYRIN and HIN domain-containing (PYHIN) protein that mediates IFN-beta induction by cytosolic DNA. Another PYHIN protein, AIM2, had been shown to be mediate 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. We are examining the role of PYHINs in human disease, 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. 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. Furthermore, we have identified peptides derived from poxviral proteins that inhibit innate immune signalling, and thus may have therapeutic use.

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 previously showed that mammalian SARM negatively regulates TRIF function in human cells, and also that SARM has TLR-independent roles, such as in chemokine induction in macrophages. SARM is also known to control cell death in neuronal cells. Currently we are investigating how SARM regulates inflammasomes and cell death pathways in macrophages.

RESEARCH TEAM

Marcin Baran, Ph.D. (Postdoctoral Fellow)
Michael Carty, Ph.D. (Postdoctoral Fellow)
Lili Gu, Ph.D. (Postdoctoral Fellow)
Ryoichi Sugisawa, Ph.D. (Postdoctoral Fellow)
Ciara Doran (Ph.D. Student)
Jamie Murphy, M.Sc. (Ph.D. student)
Katharine Shanahan (Ph.D. Student)
Laura Madrigal-Estebas, Ph.D. (Part-time lab manager)

CURRENT FUNDING

Science Foundation Ireland (SFI). .
Biotechnology and Biological Sciences Research Council (BBSRC).

CURRENT COLLABORATORS

Jose Bengoechea, Queens University Belfast, UK
David Brough, University of Manchester, UK
Emma Creagh, Trinity College Dublin
Padraic Fallon, Trinity College Dublin
Ursula Fearon, Trinity College Dublin
Kate Fitzgerald, University of Massachusetts Medical School, USA
Bostjan Kobe, University of Queensland, Australia
Ed Lavelle, Trinity College Dublin
Soren Paludan, University of Aarhus, Denmark
Andreas Pichlmair, Technical University of Munich, Germany
Neta Regev-Rudzki, Weizmann Institute of Science, Israel
Anthony Slavin & Bradford McRae, AbbVie Bioresearch Centre Inc.

PUBLICATIONS

Publications page


Last updated 18 September 2018 bbutler@tcd.ie (Email).