Greg Moseley, N. Ito, L. Wiltzer, C. L. Rowe, S. Oksayan, Aaron Bryce, Lin Fa Wang, Glenn Marsh, D. Blonde and David A. Jans
Scientific Tracks Abstracts: JAA
Successful viral infection depends on the virus? capacity to evade the host?s interferon (IFN)- mediated innate immune response, and thereby prevent the establishment in cells of an antiviral state. Viral evasion of IFN immunity is mediated by multifunctional, virus-encoded IFN-antagonist proteins, which interact with diverse host factors, including intracellular signalling and eff ector molecules of the IFN system; thus, IFN-antagonists represent potential targets for antiviral therapies, but the molecular events underlying their functions are currently poorly defi ned. Using live-cell imaging, molecular/cell biology and reverse genetics approaches with animal infection models, we have investigated the functions of the archetypal IFN-antagonist, rabies virus P protein, fi nding that it undergoes intricately regulated subcellular traffi cking involving numerous sequences for interaction with the host cell?s nuclear transport machinery, cytoskeletal components, and IFN signalling/eff ector molecules. Th rough these interactions, P-protein undergoes highly regulated nucleocytoplasmic traffi cking to target host factors in specifi c subcellular sites, and thereby regulate the traffi cking/functions of components of the IFN system by several novel mechanisms. Our in vivo studies have shown that P-protein traffi cking is a vital component of immune evasion and pathogenicity, the fi rst such demonstration for any virus; importantly we found that mutations aff ecting P-protein interactions with cellular traffi cking machinery can specifi cally attenuate virus in vivo. Th is work identifi es IFN-antagonist subcellular traffi cking/interactions as vital components in virulence, and potential therapeutic targets. IFN-antagonist traffi cking has been reported for numerous human pathogenic viruses, including Nipah/Hendra, measles and Dengue, indicating that it may represent a common target for therapies for a number of highly virulent/ lethal human diseases.
Following his PhD research at the University of Sheffi eld (UK) and WEHI (Australia), Dr Moseley was awarded a Royal Society fellowship to undertake post-doctoral research in Australia where he now heads a research team at Monash University focussed on understanding the pathogenic mechanisms of lyssaviruses including rabies, and paramyxoviruses including Nipah. His principle research interest is the role of viral protein subcellular traffi cking in immune evasion, and his main research fi ndings in this area have included the fi rst demonstrations of a role for microtubules in viral immune evasion, and of the importance of viral protein traffi cking to virulence in vivo.