Theme 6: Asthma, inflammation and viral infections

Supervisors:

  Dr Rheena Ghildyal (A/Professor Phil Bardin and Professor David Jans)
  T: 9905 1220
  E: Rheena.Ghildyal@med.monash.edu.au

Project 1: Inhibition of nucleocytoplasmic trafficking by Rhinovirus proteases: relevance to asthma

Rhinoviruses (RVs) are the major cause of viral-induced exacerbation of asthma; viral-induced exacerbations are associated with 4 deaths every week in Victoria and 16 every week nationally. To date, the molecular mechanisms of RV pathogenesis are not understood, however, and current treatments are inadequate. Recent findings indicate that RV pathology in asthma may relate strongly to the inhibition of host cell nucleocytoplasmic trafficking, resulting in perturbation of host cell functions such as transcription and translation; the basis of this inhibition in RV-infected cells may be the degradation of certain components of the nuclear pore complexes (NPCs) by RV proteases. Importantly, we recently showed that RV 3C protease is localised to the nucleus in transfected cells, and can directly disrupt active and passive transport across the nuclear envelope, presumably by degrading NPC components. We aim to examine the mechanisms underlying the inhibition of nucleocytoplasmic transport by RV 3C protease in primary cells from asthmatic airways compared to non-asthmatic airways.. This should lead to an increased understanding of the role of 3C protease in RV pathology in asthma and may reveal targets for the design of therapeutics to combat RV infection/asthma exacerbations. Main techniques to be used are recombinant DNA technology, mammalian cell transfections, quantitative confocal laser scanning microscopy and in vitro nuclear transport assays, in addition to virology and immunochemical techniques.