VIRAL IMMUNE EVASION RESEARCH
Prof Andrew Bowie
Prof Andrew Bowie, PhD
Phone: +353-1-8962435
Fax: +353-1-6772400
Email: agbowie@tcd.ie
Location: Room 3.09 Biotechnology Building |
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Research Interests
1. Mechanisms employed by Vaccinia Virus (VACV) to evade and modulate the host
innate immune response.
Studying the mechanisms whereby viruses evade and neutralise the host immune system has yielded valuable insights as to how the host immune machinery functions, since viruses often specifically target key points of regulation of immunity. For example, 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. The VV genome is 190kb and encodes over 200 ORFs, many of which have no known function. Given that approx 50 % of the known ORFs are involved in host control and immunosuppression with both intra- and extra-cellular host targets, it is likely that many such poxvirus immune evasion strategies remain to be discovered. Therefore VACV represents a powerful but still under-exploited 'toolbox' with which to probe the molecular mechanisms of immunity. Pattern recognition receptors (PRRs) which induce IFN production have been identified as Toll-like receptors (TLRs), RIG-like receptors (RLRs) and cytosolic DNA receptors. All viruses need to suppress the interferon (IFN) response in order to successfully become established in a host, and using functional screens we have identified novel VACV IFN inhibitors which target these 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.
2. Interactions between VACV and TLR signalling.
TLRs are members of the IL1R/TLR superfamily, and have been shown to act as PRRs, leading to pathogen recognition, and activation of innate and adaptive immunity. TLRs are also implicated in autoimmune and inflammatory diseases. We have identified two VACV proteins, A46R and A52R, that can not only antagonise intracellular TLR signalling, but also subvert these pathways for the benefit of the virus. Current on-going investigations are seeking to characterise the mechanism of inhibition of TLR signalling by A46R and A52R, and to exploit the therapeutic potential of peptides derived from them.
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 have shown that the fifth member of the adapter family, SARM, negatively regulates TRIF function in human cells. Further, SARM protein is upregulated by TLR ligands. SARM is highly conserved across different organisms, and may have further functions. Currently we are exploring the mechanisms whereby SARM is regulated, how SARM causes inhibition of the TRIF pathway, and whether SARM has other functions.
4. The role of IRAK-2 in TLR signalling
Although discovered in 1997, 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, and have suggested that IRAK-2 is the key NFkappaB-activating IRAK, while IRAK-1 is fundamentally more important for IFN regulatory factor (IRF) activation. Currently the mechanism whereby IRAK-2 participates in NFkappaB activation is being explored.
Together, these studies are providing important insights into the molecular mechanisms whereby the immune system senses and responds to viruses.
Research Personnel
Postdoctoral Fellows:
Michael Carty, PhD
Sinead Keating, PhD
Julianne Stack, PhD
Leonie Unterholzner, PhD
Kiva Brennan, PhD
Graduate students:
Sinead Flannery, BA
Tatyana Lysakova, BA
Orla Mulhern, BA
Marcin Baran, MSc
Claudia Gurtler, MSc
Lab manager (part-time):
Geraldine Brosnan, PhD
Funding
Science Foundation Ireland
The Health Research Board
Collaborators
Dr Amir Khan, Trinity College Dublin
Dr Kate Fitzgerald, University of Massachusetts Medical School, MA
Dr Felix Randow, MRC Laboratory of Molecular Biology, Cambridge
Dr Soren Riis Paludan, University of Aarhus, Denmark
Prof. Geoffrey Smith, Imperial College School of Medicine, London
Recent Publications by Andrew Bowie and the Viral Immune Evasion group
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