Development of a mouse model for post-polio-like syndrome by using pseudo poliovirus

我们用脊髓灰质炎病毒(PV)伪病毒感染表达PV受体的小鼠(TgPVR21)建立了残留脊髓灰质炎样麻痹的小鼠模型，并分析了瘫痪对小鼠的长期影响。为了确定脊髓灰质炎后综合征可能需要的宿主因素，我们寻找了抑制PV复制过程的ANT-PV化合物。TgPVR21小鼠接种4.1×106个以上感染单位的PV伪病毒后，出现严重的残留脊髓灰质炎样麻痹。在有/无运动应激的6个月后，我们不能识别可归因于瘫痪和运动应激的脊髓灰质炎后症状。我们确定GW5074(Raf-1抑制剂)为PV复制抑制因子，以及几种能与GW5074协同作用抑制PV复制的激酶抑制剂，包括MEK1/2抑制剂、EGFR抑制剂、PI3K抑制剂。我们发现，GW5074的病毒抗性决定因素是一个类似于一种抗微小病毒化合物环维新的突变，其抑制机制未知。此外，我们确定磷脂酰肌醇4-激酶IIIβ(PI4KB)是GW5074抗PV活性的靶点，并指出PI4KB是环境辛类化合物抗PV活性的靶点。

We established a mouse model that shows residual poliomyelitis-like paralysis by using poliovirus (PV) pseudovirus infection in PV receptor-expressing mouse (TgPVR21), and analyzed a long-term effect of paralysis in the mice. To identify\y possible host factor required for post-polio syndrome, we searched for ant-PV compounds that inhibit replication process of PV. TgPVR21 mice showed severe residual poliomyelitis-like paralysis after inoculation with PV pseudovirus of more than 4.1×10^6 infectious units. After 6 months with/without exercise stress, we could not identify post-polio like symptom that could be attributable to the paralysis and exercise stress. We identified GW5074 (Raf-1 inhibitor) as PV replication inhibitor, and several kinase inhibitors, including MEK1/2 inhibitors, EGFR inhibitor, PI3K inhibitor, that could cooperatively act with GW5074 to inhibit PV replication. We found that the viral resistance determinant to GW5074 was a similar mutation to an anti-picornavirus compound enviroxime with unknown inhibitory mechanism. Moreover, we identified phosphatidylinositol 4-kinase III beta (PI4KB) as the target of GW5074 for its anti-PV activity, and indicated that PI4KB is a target of enviroxime-like compounds for its anti-PV activity.