Studies on interferon response-restricted tropism of neurotripic viruses

脊髓灰质炎病毒（PV）和泰勒鼠脑脊髓炎病毒（TMEV）是嗜神经病毒，在中枢神经系统中有效复制。我们研究了这些病毒的组织特异性致病性和组织中干扰素反应之间的关系。从PV和TMEV感染小鼠模型和缺乏I型IFN受体基因的小鼠的结果中，我们发现非神经组织受到病毒感染后诱导的IFN和IFN刺激基因（ISGs）的保护，而病毒在神经组织中进行复制，因为IFN反应不顺从.非神经组织暴露于血液中的自发性IFN，即使病毒感染没有发生，并且一旦在外周组织的某处发生感染，它们容易暴露于诱导的IFN。由于这些原因，非神经组织中ISG的表达水平保持在相对高的水平。相反，由于血脑屏障的阻断，神经组织不容易暴露于血清IFN。神经组织中的IFN反应不像非神经组织那样活跃. PV能在非神经组织来源的单层培养细胞中复制，而在体内不能复制。我们发现，当细胞在体外培养时，IFN应答所必需的ISGs的表达水平降低时，病毒复制成为可能，因此，IFN应答对病毒复制的调节是决定病毒复制的最重要因素之一。我们在这里展示了一种新的机制，确定组织嗜性限制IFN反应。

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.