Studies on interferon response-restricted tropism of neurotripic viruses

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Poliovirus (PV) and Theiler's murine encephalomyelitis virus (TMEV) are neurotropic viruses that replicate efficiently in the central nervous system. We investigated the relationship between the tissue-specific pathogenicity of these viruses and the interferon response in tissues.1. From the results of PV and TMEV infection in mouse model and mice that lack the type I IFN receptor gene, we found that non-neural tissues are protected from infection by IFN and IFN-stimulated genes (ISGs) induced upon virus infection, whereas virus replication proceed in the neural tissues because the IFN response are not sufficient.2. The non-neural tissues are exposed to the spontaneous IFNs in the blood even when virus infection does not occur, and they are readily exposed to the induced IFNs once infection occurs at somewhere in the peripheral tissues. For these reasons, expression levels of ISGs in the non-neural tissues are kept at relatively high. On the contrary, neural tissues are not easily exposed to the serum IFNs by the blockage of blood-brain barrier. IFN response in the neural tissues is not active as in the non-neural tissues.3. PV can replicate in the monolayer cultured cells derived from non-neural tissues while it cannot in vivo. We found that virus replication became possible as the expression levels of the ISGs that are necessary for IFN response decreased when the cells are cultivated in vitro.As a conclusion, permissivity modulated by the IFN response is one of the most important factors that determine the virus replication. We show here a novel mechanism that determines tissue tropism restricted by IFN response.