Key Laboratory of Prevention and Control Agents for Animal Bacteriosis (Ministry of Agriculture and Rural Affairs), Hubei Provincial Key Laboratory of Animal Pathogenic Microbiology, Institute of Animal Husbandry and Veterinary, Hubei Academy of Agricultural Sciences, Wuhan 430064, China.
Viruses. 2023 Feb 14;15(2):534. doi: 10.3390/v15020534.
Japanese encephalitis virus (JEV) infection causes host endoplasmic reticulum stress (ERS) reaction, and then induces cell apoptosis through the UPR pathway, invading the central nervous system and causing an inflammation storm. The endoplasmic reticulum stress inhibitor, 4-phenyl-butyric acid (4-PBA), has an inhibitory effect on the replication of flavivirus. Here, we studied the effect of 4-PBA on JEV infection both in vitro and vivo. The results showed that 4-PBA treatment could significantly decrease the titer of JEV, inhibit the expression of the JEV NS3 protein (in vitro, < 0.01) and reduce the positive rate of the JEV E protein (in vivo, < 0.001). Compared to the control group, 4-PBA treatment can restore the weight of JEV-infected mice, decrease the level of IL-1β in serum and alleviate the abnormalities in brain tissue structure. Endoplasmic reticulum stress test found that the expression level of GRP78 was much lower and activation levels of PERK and IRE1 pathways were reduced in the 4-PBA treatment group. Furthermore, 4-PBA inhibited the UPR pathway activated by NS3, NS4b and NS5 RdRp. The above results indicated that 4-PBA could block JEV replication and inhibit ER stress caused by JEV. Interestingly, 4-PBA could reduce the expression of NS5 by inhibiting transcription ( < 0.001), but had no effect on the expression of NS3 and NS4b. This result may indicate that 4-PBA has antiviral activity independent of the UPR pathway. In summary, the effect of 4-PBA on JEV infection is related to the inhibition of ER stress, and it may be a promising drug for the treatment of Japanese encephalitis.
日本脑炎病毒（JEV）感染会引起宿主内质网应激（ERS）反应，然后通过 UPR 途径诱导细胞凋亡，侵入中枢神经系统并引起炎症风暴。内质网应激抑制剂 4-苯丁酸（4-PBA）对黄病毒的复制具有抑制作用。在这里，我们研究了 4-PBA 在体外和体内对 JEV 感染的影响。结果表明，4-PBA 处理可显著降低 JEV 的滴度，抑制 JEV NS3 蛋白的表达（体外， < 0.01）并降低 JEV E 蛋白的阳性率（体内， < 0.001）。与对照组相比，4-PBA 处理可恢复 JEV 感染小鼠的体重，降低血清中 IL-1β 的水平，并缓解脑组织结构的异常。内质网应激试验发现，4-PBA 处理组 GRP78 的表达水平较低，PERK 和 IRE1 途径的激活水平降低。此外，4-PBA 抑制了 NS3、NS4b 和 NS5 RdRp 激活的 UPR 途径。上述结果表明，4-PBA 可以阻断 JEV 的复制并抑制 JEV 引起的内质网应激。有趣的是，4-PBA 通过抑制转录降低 NS5 的表达（ < 0.001），但对 NS3 和 NS4b 的表达没有影响。这一结果可能表明 4-PBA 具有独立于 UPR 途径的抗病毒活性。综上所述，4-PBA 对 JEV 感染的作用与抑制内质网应激有关，它可能是治疗日本脑炎的一种有前途的药物。
