Although at present there is insufficient data available from human HeV cases to conclude whether neuroinvasion by the olfactory sensory neuron pathway is of primary pathogenetic importance in this species, we do note that the most likely route of human infection is contact droplet infection of the nasopharynx, and so exposure by this route is plausible. More importantly, the pattern of spread of HeV through the brain of mice is best explained by an ability of the virus to employ direct trans-neuronal transmission without concomitant generation of an infectious virion: these observations are of key pathogenetic significance to the human disease. Not only do they provide a possible explanation for failure to reisolate HeV from both sub-acute (I. Smith, unpublished data) and recrudescent [38] human cases of HeV using conventional techniques and in whom there was ample evidence of its ongoing replication, they raise important challenges to optimizing therapeutic interventions. A significant difference in response to infection is seen between aged and juvenile mice where aged mice appear to have a greater propensity to develop clinical disease compared with juvenile animals. A similar trend has been noted for other viral infections of mice, most notably SARS infection. In this case aged mice were susceptible to clinical disease development after challenge with SARS while their juvenile counterparts were not [40] . This observed difference in response to HeV infection between juvenile and aged mice can be used to model and investigate the mechanisms whereby age may affect clinical outcome.