The study investigating the susceptibility of BALB/c strain mice to HeV infection described above revealed that four out of five aged mice had viral RNA in lung tissue as late as 21 DPI in the absence of clinically apparent respiratory disease or detectable pulmonary pathology at euthanasia. In light of these findings, a time-course study was performed to evaluate whether infection of the upper and lower respiratory tracts developed in aged mice following HeV exposure. Aged BALB/c mice exposed to HeV by the intranasal route were euthanased at each time point of the following schedule; two mice every 48 hours from 1-14 DPI, two mice every 72 hours from 15 to 23 DPI, and three mice at 28 days PI, or on development of clinical disease according to predetermined humane endpoints defined from the previous study. Whole brain, lung, nasal turbinates and other tissue samples were examined by histology and immunohistochemistry. Lung tissue was further analysed for presence of viral genome and live infectious virus by qPCR and virus isolation, respectively (Table 4) . Mice sampled between days 6 and 14 pi were positive for HeV viral antigen in bronchoalveolar tissue, but antigen deposits were both dense and focal and it was not possible to distinguish on morphologic grounds whether alveolar lining cells, alveolar interstitium, or endothelial cells were involved. Live virus was reisolated from the lungs of mice sampled between 4 and 10 DPI (Table 4 ) consistent with transient infection of the lower respiratory tract after intranasal exposure to HeV. The viral titres detected were comparatively low with a maximum titre (10 2.3 TCID 50) recovered from a mouse on day 6. Interestingly, HeV antigen deposition in lung ( Figure 1D ) was not associated with detectable bronchoalveolitis and pulmonary vasculitis was not identified. In the upper respiratory tract, immunopositive cellssometimes accompanied by small focal necrotising inflammatory lesions (Figure1E and 1F), were detected in olfactory mucosa of mice between 6 to 17 DPI. It was not determined whether cells involved were supporting cells, basal cells or olfactory sensory neurons.