Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
Molecules. 2018 Dec 18;23(12):3346. doi: 10.3390/molecules23123346.
Japanese encephalitis is a zoonotic disease caused by the Japanese encephalitis virus (JEV). It is mainly epidemic in Asia with an estimated 69,000 cases occurring per year. However, no approved agents are available for the treatment of JEV infection, and existing vaccines cannot control various types of JEV strains. Drug repurposing is a new concept for finding new indication of existing drugs, and, recently, the concept has been used to discover new antiviral agents. Identifying host proteins involved in the progress of JEV infection and using these proteins as targets are the center of drug repurposing for JEV infection. In this study, based on the gene expression data of JEV infection and the phenome-wide association study (PheWAS) data, we identified 286 genes that participate in the progress of JEV infection using systems biology methods. The enrichment analysis of these genes suggested that the genes identified by our methods were predominantly related to viral infection pathways and immune response-related pathways. We found that bortezomib, which can target these genes, may have an effect on the treatment of JEV infection. Subsequently, we evaluated the antiviral activity of bortezomib using a JEV-infected mouse model. The results showed that bortezomib can lower JEV-induced lethality in mice, alleviate suffering in JEV-infected mice and reduce the damage in brains caused by JEV infection. This work provides an agent with new indication to treat JEV infection.
日本脑炎是一种由日本脑炎病毒（JEV）引起的人畜共患病。它主要在亚洲流行，估计每年有 69000 例病例。然而，目前还没有针对 JEV 感染的批准药物，现有的疫苗也不能控制各种类型的 JEV 株。药物再利用是一种寻找现有药物新适应症的新概念，最近，该概念已被用于发现新的抗病毒药物。确定参与 JEV 感染进展的宿主蛋白，并将这些蛋白作为靶点，是 JEV 感染药物再利用的核心。在这项研究中，我们基于 JEV 感染的基因表达数据和表型全基因组关联研究（PheWAS）数据，使用系统生物学方法鉴定了 286 个参与 JEV 感染进展的基因。这些基因的富集分析表明，我们方法鉴定的基因主要与病毒感染途径和免疫反应相关途径有关。我们发现，硼替佐米可以靶向这些基因，可能对 JEV 感染的治疗有效果。随后，我们使用 JEV 感染的小鼠模型评估了硼替佐米的抗病毒活性。结果表明，硼替佐米可以降低 JEV 诱导的小鼠致死率，减轻 JEV 感染小鼠的痛苦，并减少 JEV 感染引起的大脑损伤。这项工作为治疗 JEV 感染提供了一种新的药物。
