Intranasal infection of Rift Valley fever virus in the ferret model suggests multiple routes of neuroinvasion with consequential encephalitis and ophthalmitis

Rift Valley fever virus (RVFV) causes haemorrhagic fever, ophthalmitis, and in severe cases, encephalitis in humans. Despite the well-recognised neurotropism, the mechanisms of central nervous system (CNS) invasion remain poorly understood. We investigated RVFV ingress into the CNS and resulting neuropathogenesis following intranasal inoculation in ferrets (Mustela putorius furo) (n = 15). At 3 DPI, before RVFV dissemination to the CNS, mild multifocal suppurative rhinitis and multifocal interstitial pneumonia were detected in the nasal cavity and lungs respectively, supported by detection of viral antigen and genome. From 6 DPI, infected ferrets exhibited neurological signs; by 6 - 8 DPI, a mild-to-moderate non-suppurative meningoencephalitis and myelitis was observed, progressing rostrally to caudally, with ophthalmitis observed from 7 DPI and 100% mortality by 8 DPI. Mild-to-moderate hyperaemia of the meninges was identified macroscopically in all infected ferrets. An immune response to infection was unable to prevent neuropathogenesis and clinical disease. Although our results suggest that neuroinvasion occurs via the olfactory route through the nasal turbinates to cranial nerves, virus replication in the lungs and presence of viremia implies that haematogenous dissemination into the CNS as a secondary route is possible. This relevant experimental ferret model may further contribute to understanding the pathogenesis of human RVFV infection.