Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Flaviviruses are small viruses and a leading cause of morbidity and mortality worldwide. Most are transmitted by arthropod vectors (mosquitoes or ticks) including West Nile virus (WNV), Tick-borne encephalitis virus (TBEV) and Saint Louis encephalitis virus (SLEV) all of which can cause serious neurological disease. With the exception of TBEV, there are no vaccines or therapies for these viruses and new treatments are desperately needed. To gain access to the central nervous system, encephalitic flaviviruses must breach the tight-junctions (TJs) of the blood-brain barrier. The Hobman laboratory at the University of Alberta recently reported that WNV modulates TJs by inducing degradation of two TJ proteins. Given that breaching the TJs of the blood-brain barrier is a key aspect of virus-induced neuropathogenesis, the objective of this study is to elucidate the mechanism by which WNV (and other encephalitic flaviviruses) modulates cellular pathways that control the barrier function of TJs. The underlying hypothesis for my research is that encephalitic flaviviruses employ a conserved mechanism to manipulate TJs in their hosts. Recent evidence suggests that degradation of the TJs is dependent on expression of a cellular protein, LNX1p80, that is upregulated in WNV infected cells. Additionally, further experiments suggest the WNV NS4A protein is the sole virus encoded entity required for this process. This study aims to first determine how WNV infection and NS4A expression affects the composition and architecture of TJs and secondly, elucidate the mechanism by which NS4A induces degradation of TJ integral membrane proteins. Through these studies, we hope to identify novel targets for anti-viral therapy to prevent neurological disease in flavivirus-infected patients. In addition, my studies may provide the basis for design of live attenuated recombinant vaccines that pose no risk of neurovirulence.