TRANSNEURONAL SPREAD OF SEMLIKI-FOREST-VIRUS IN THE DEVELOPING MOUSE OLFACTORY SYSTEM IS DETERMINED BY NEURONAL MATURITY

Many neurotropic virus infections have been shown to be virulent in ne onatal and suckling mice bur 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 ha s been shown to be independent of specific immune responses. During th e 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, sp read and virulence we have studied the course of infection in the mous e olfactory system. The olfactory system is well-characterized with re gard to its development and neuroanatomy and represents an important r oute of entry of many neurotropic viruses. Following Semliki Forest vi rus infection, mice younger than 14 days-of-age died from a fulminant panencephalitis, whilst those 15 days and older survived and cleared t he infection. Microscopic examination of brains from mice inoculated i ntranasally either bilaterally or unilaterally and stained by in situ hybridization to detect viral RNA revealed spread of infection along n eurites in a circuit-specific manner. Spread in the main olfactory bul b and to primary, secondary and tertiary olfactory connections was obs erved. 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 retro grade axonal spread were observed. During the first three postnatal we eks the rate and extent of virus spread decreased with increasing age. Spread of infection between specific structures was closely related t o neuronal maturation. As olfactory system connections matured transmi ssion of virus was curtailed. In mice inoculated at six weeks or six m onths-of-age infection was minimal in and rarely observed beyond the c ontinually renewed olfactory nerve layer. The ability of this virus to replicate and, or spread in the CNS is clearly linked to neuronal mat uration. (C) 1997 IBRO.