Lyssaviruses, including rabies virus and Australian bat lyssavirus are a globally distributed genus of zoonotic pathogens that cause rabies disease with a case-fatality rate in humans of 100%, resulting in over 70,000 deaths/year.
In the search for new targets to combat rabies, we have undertaken a major research program to define the intracellular interface formed by lyssaviruses with the host. This research has shown that lyssaviruses form a complex array of interactions with diverse cellular factors, and clearly indicated that the viral P-protein is the major player in this interface, apparently acting as a central hub of virus-host molecular interactions. Importantly, our recent research has indicated critical roles for these interactions in the development of disease in vivo. In particular, we identified the likely site of interaction of P-protein with STAT transcription factors of the innate antiviral immune response system. Mutation of this site (a hydrophobic pocket called the W-hole) had no impact on viral genome replication, but prevented viral subversion of innate immune signalling to render virus exquisitely sensitive to interferon. Introduction of these mutations to a normally 100% lethal recombinant virus strain prevented the onset of disease in mice, identifying this site as a potential target for therapies or viral attenuation.
We have now begun to exploit this new knowledge in programs aiming to develop new live attenuated vaccine strains and antiviral drugs. We are using reverse genetics/animal infection models to assess the potency and safety of modified vaccine strains, and structural biology/fragment screening methodologies to identify new compounds that may be developed toward leads in the search for novel antivirals. The presentation will introduce our new mechanistic insights into the key molecular mechanisms underlying lethal rabies disease, and current progress toward the development of new therapeutic approaches targeting these mechanisms.