Transneuronal spread of Semliki Forest virus in the developing mouse olfactory system is determined by neuronal...

Many neurotropic virus infections have been shown to be virulent in neonatal and suckling mice but avirulent in weaned mice. The neurotropic alphavirus Semliki Forest virus is a well-studied example of this and importantly the age-related change in neurovirulence of this virus has been shown to be independent of specific immune responses. During the first two postnatal weeks many major physiological changes including axonogenesis, synaptogenesis and myelination occur within the rodent CNS. To investigate whether these changes affect virus replication, spread and virulence we have studied the course of infection in the mouse olfactory system. The olfactory system is well-characterized with regard to its development and neuroanatomy and represents an important route of entry of many neurotropic viruses. Following Semliki Forest virus infection, mice younger than 14 days-of-age died from a fulminant panencephalitis, whilst those 15 days and older survived and cleared the infection. Microscopic examination of brains from mice inoculated intranasally either bilaterally or unilaterally and stained by in situ hybridization to detect viral RNA revealed spread of infection along neurites in a circuit-specific manner. Spread in the main olfactory bulb and to primary, secondary and tertiary olfactory connections was observed. In neonatal mice virus rapidly spread throughout the olfactory system and the temporal progress of the infection correlated with the known connectivity patterns of this system. Both anterograde and retrograde axonal spread were observed. During the first three postnatal weeks the rate and extent of virus spread decreased with increasing age. Spread of infection between specific structures was closely related to neuronal maturation. As olfactory system connections matured transmission of virus was curtailed. In mice inoculated at six weeks or six months-of-age infection was minimal in and rarely observed beyond the continually renewed olfactory nerve layer. The ability of this virus to replicate and, or spread in the CNS is clearly linked to neuronal maturation.