In summary, this paper reports three novel observations. Firstly, mice are susceptible to HeV infection after intranasal exposure with aged animals reliably developing encephalitic disease. Their small size and ease of handling, as well as the vast range of biological reagents available for use in the species, render them highly valuable infection models for HeV encephalitis. Secondly, our data strongly support a role for not only anterograde neuroinvasion along sensory neurones but also transneuronal viral spread of HeV within the brain. This finding is of particular importance as infection may be established within the nervous system before current systemic treatments are able to be delivered across the blood-brain barrier. Lastly, mice are resistant to systemic vasculitis and fulminating HeV disease, the mechanisms of which can be explored with therapeutic potential. These findings provide a significant contribution to the body of knowledge in the field and have opened up new areas of investigation, from which significant understanding and further research can arise of benefit to humans as well as animals.