Viral Replication in Olfactory Receptor Neurons and Entry into the Olfactory Bulb and Brain^a

Abstract

This communication describes our ongoing studies of the interaction of the mouse host and vesicular stomatitis virus (VSV). When VSV is applied to the nasal neuroepithelium, it initially replicates in olfactory receptor neurons, and is transmitted along the olfactory nerve to the central nervous system (CNS) within 12 hours. In the olfactory bulb, the virus replicates invasively through the layers of the olfactory bulb, reaching the olfactory ventricle by day 4-5 post infection, and the hindbrain by day 8 post infection. In mice, infection may result in a 50% mortality rate. The crucial host innate and specific immune responses responsible for restricting viral propagation and caudal spread of the virus will be discussed. The efficacy of interleukin-12 (IL-12) treatment for enhanced viral clearance and promotion of host recovery are described along with the implications for treatment of human encephalitis. The hosts' response to infection is also regulated by the sex of the host, and the age at infection. The role of specific mucosal humoral immunity and systemic cellular immunity in prevention of infection are described.

Local Type I IFN Receptor Signaling Protects against Virus Spread within the Central Nervous System

“…Because virus could not be reisolated from surviving mice, these results proved clearance of virus in the brains of the surviving mice (9). Thus far, it is unclear how exactly virus clearance is accomplished within the brain.…”

“…high-dose infection of WT mice, VSV can be detected in brains of virtually all infected animals, whereas only 50% of the animals eventually died, indicated that virus infection was controlled within the CNS (9). Although administration of high-dose IFN after i.n.…”

“…(8). Viral proteins are found in deeper layers of the olfactory bulb and the ventricular system by day 4 (9). Having reached the olfactory bulb, VSV spreads transsynaptically using both anterograde and retrograde transport to other regions of the brain (7) and most likely via cerebrospinal fluid (10).…”

“…Having reached the olfactory bulb, VSV spreads transsynaptically using both anterograde and retrograde transport to other regions of the brain (7) and most likely via cerebrospinal fluid (10). Virus-associated pathology can be recognized in the spinal cord and is associated with hind limb paralysis (9,11).…”

“…infection is most likely due to the fact that upon i.n. inoculation VSV can readily infect olfactory receptor neurons (7,9). Because the cell body of olfactory receptor neurons is located in the nasal mucosa, whereas their axons project into the olfactory bulb, virus can easily enter the CNS (12).…”