P106 Non-redundant in vivo functions of IFN-β protect against virus infection within the central nervous system

Abstract

Introduction Previous studies showed that type I interferon receptor (IFNAR) triggering is critically required to control many different virus infections. In mice one IFN- β and 14 different IFN- α isotypes interact with IFNAR. Infection experiments with peripherally challenged IFN- β −/− mice did not reveal any overt phenotype suggesting that IFN- α and IFN- β played a redundant role under such conditions. Here we readdressed IFN- β function under conditions of intranasal (i.n.) virus infection. Methods IFN- β −/− and C57BL/6 mice were i.n. and i.v. infected with vesicular stomatitis virus (VSV) and their survival monitored. Serum IFN titers were determined by an ELISA method. Additionally reporter mice for the scrutiny of IFN- β expression (IFN- β Δ βluc / WT ) and IFNAR signaling (ISRE-eGFP) were used for in vivo and ex vivo analysis. Results Upon i.n. VSV infection IFN- β −/− mice showed a significantly enhanced vulnerability to lethal VSV infection. A previous study revealed that upon i.n. VSV instillation of C57BL/6 mice the virus readily infected olfactory sensory neurons and moved along axons into the glomerular layer of the olfactory bulb, where it was arrested in an IFNAR-dependent manner. After i.v. as well as i.n. VSV infection IFN- α , but no IFN- β , was detected in the serum. Analysis of IFN- β reporter mice revealed that within the central nervous system (CNS) protective IFN- β was induced primarily in the olfactory bulb, presumably by neurons. Interestingly, locally produced IFN- β was active also in distal brain areas as evidenced by induction of GFP expression in the cerebrum of i.n. infected ISRE-eGFP reporter mice. Of note ISRE-eGFP mice intercrossed with IFN- β −/− mice did not show local IFNAR signaling within the CNS. Conclusion In conclusion our experiments are in accordance with the model that upon virus infection of the CNS IFN- β responses are selectively induced within the olfactory bulb that stimulate also distal brain areas, whereas IFN- α s are primarily induced in the periphery and there account for protection of peripheral tissues.