Zoonotic wildlife diseases pose significant health risks not only to their primary vectors but also to humans and domestic animals. Rabies is a lethal encephalitis caused by rabies virus (RV). This RNA virus can infect a range of terrestrial mammals but each viral variant persists in a particular reservoir host. Active management of these host vectors is needed to minimize the negative impacts of this disease, and an understanding of the immune response to RV infection aids strategies for host vaccination. Current knowledge of immune responses to RV infection comes primarily from rodent models in which an innate immune response triggers activation of several genes and signalling pathways. It is unclear, however, how well rodent models represent the immune response of natural hosts. This study investigates the innate immune response of a primary host, the raccoon, to a peripheral challenge using the raccoon rabies virus (RRV). The extent and temporal course of this response during RRV infection was analysed using genes predicted to be upregulated during infection (IFNs; IFN regulatory factors; IL-6; Toll like receptor-3; TNF receptor). We found that RRV activated components of the innate immune system, with changes in levels of transcripts correlated with presence of viral RNA. Our results suggest that natural reservoirs of rabies may not mimic the immune response triggered in rodent models, highlighting the need for further studies of infection in primary hosts.

Rabies virus presents a global public health problem. Our current understanding of the molecular determinants of rabies virulence stems from rodent models and laboratory strains of the virus, however, it is unclear how well rodent models represent viral response in natural reservoirs. Here, we examined interactions between the raccoon variant of rabies virus (RRV) and its natural host, raccoons, to gain a better understanding of molecular determinants of virulence in this system. We found expression patterns of RRV genes under tight control until the virus reached the central nervous system where replication increased significantly. Further, our examination of viral variants within an individual revealed that variant diversity may have an effect on virulence. We found that a mutation at a region of a T helper cell epitope on the nucleoprotein was associated with viral challenge outcomes and could be associated with RRV pathogenicity.