Rabies virus (RABV) and other members of the Lyssavirus genus are the causative agents of rabies disease, a lethal neurological disease that is 100% fatal following the onset of clinical symptoms. Despite being vaccine preventable, an estimated 60,000 deaths occur each year, primarily due to limited vaccine access, complicated vaccination regimes and unapparent exposure. As no anti-viral therapeutics exist, there is an urgent need to identify molecular targets for the development of novel therapeutics or improved attenuated vaccines. Evasion of innate antiviral immunity provides a number of exciting possibilities in this respect, but progress is hindered by major gaps in our knowledge of the underlying mechanism.
The ability of RABV and related lyssaviruses to establish a productive infection and cause disease is intimately linked to its capacity to evade the host immune response. The viral phosphoprotein (P) has been shown to be a critical pathogenicity factor, required for viral evasion by antagonism of type I interferon (IFN) induction and signalling. The importance of this multi-faceted evasion strategy has been illuminated in vitro and in vivo; however, the mechanism by which P protein blocks IFN induction remains unresolved. Using comparative analysis of rabies virus, lyssavirus and related mutated variants thereof, we have defined significant variation in the antagonistic function of P, and developed point mutations able to disable this function in protein and infection studies. This is allowing us to identify key sequence determinants of antagonism and, using quantitative proteomics approaches, to define molecular candidates targeted by the virus for immune escape.
This study should help us to identify potential new targets for the generation of attenuated vaccine strains lacking IFN antagonist function, and potentially antiviral compounds to treat this currently incurable disease.