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

我们通过使用脊髓灰质炎病毒（PV）假病毒感染表达PV受体的小鼠（TgPVR 21）建立了显示残留脊髓灰质炎样瘫痪的小鼠模型，并分析了瘫痪在小鼠中的长期影响。为了确定脊髓灰质炎后综合征所需的可能的宿主因子，我们寻找抑制PV复制过程的抗PV化合物。TgPVR 21小鼠在接种超过4.1×10^6感染单位的PV假病毒后表现出严重的残留脊髓灰质炎样瘫痪。在有/无运动应激6个月后，我们无法确定可能归因于瘫痪和运动应激的脊髓灰质炎后样症状。我们鉴定出GW 5074（Raf-1 inhibitor）为PV复制抑制剂，并发现几种激酶抑制剂，包括MEK 1/2抑制剂、EGFR抑制剂、PI 3 K抑制剂，可与GW 5074协同作用抑制PV复制。我们发现病毒对GW 5074的抗性决定簇是一个与抗小核糖核酸病毒化合物enviroxime相似的突变，其抑制机制未知。此外，我们鉴定了磷脂酰肌醇4-激酶III β（PI 4KB）作为GW 5074的抗PV活性的靶标，并且表明PI 4KB是环肟样化合物的抗PV活性的靶标。

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.