Studies on interferon response-restricted tropism of neurotripic viruses

脊髓灰质炎病毒（PV）和Theiler小鼠脑脊髓炎病毒（TMEV）是在中枢神经系统中有效复制的嗜神经病毒。我们研究了这些病毒的组织特异性致病性与组织中的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来看，我们发现非神经组织不受病毒感染后诱导的IFN和IFN刺激基因（ISGs）的感染，而病毒复制在神经组织中进行，因为IFN反应不充分。即使没有发生病毒感染，非神经组织也会暴露于血液中自发的ifn，一旦感染发生在外周组织的某个地方，它们也很容易暴露于诱导的ifn。因此，isg在非神经组织中的表达水平相对较高。相反，由于血脑屏障的阻塞，神经组织不易暴露于血清IFNs。IFN在神经组织中的反应不像在非神经组织中那样活跃。PV可以在非神经组织的单层培养细胞中复制，而在体内不能复制。我们发现，当体外培养细胞时，IFN应答所必需的isg表达水平降低，病毒复制成为可能。综上所述，由干扰素反应调节的容许度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，决定受IFN反应限制的组织向性。

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.