Liu Juan, Jing Wenxian, Fang Yongxiang, He Xiaobing, Chen Guohua, Jia Huaijie, Wang Jingyu, Jing Zhizhong
State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Agriculture Ministry Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
College of Veterinary Medicine, Northwest A&F University, Yangling, China.
Front Microbiol. 2022 Mar 3;12:823825. doi: 10.3389/fmicb.2021.823825. eCollection 2021.
The Japanese encephalitis virus (JEV) is a leading cause of mosquito-borne viral encephalitis worldwide. Clinical symptoms other than encephalitis, on the other hand, are substantially more prevalent with JEV infection, demonstrating the relevance of peripheral pathophysiology. We studied the peripheral immunopathogenesis of JEV using IFNAR deficient (IFNAR) mice infected with the SA14-14-2 strain under the BSL-2. The body weight and survival rate of infected-IFNARmice decreased significantly. Infected-IFNARmice's liver and spleen demonstrated obvious tissue damage and inflammatory cell infiltration. There was also extensive viral replication in the organs. IFN-α/β protein expression was dramatically elevated in peripheral tissues and serum, although the related interferon-stimulated genes (ISGs) remained low in the spleen and liver of infected-IFNARanimals. Consistently, the differentially expressed genes (DEGs) analysis using RNA-sequencing of spleens showed inflammatory cytokines upregulation, such as IL-6, TNF-α, and MCP-1, and IFN-γ associated cytokine storm. The infiltration of macrophages and neutrophils in the spleen and liver of SA14-14-2-infected IFNAR mice was dramatically elevated. However, there was no significant difference in tissue damage, viral multiplication, or the production of IFNα/β and inflammatory cytokines in the brain. Infection with the JEV SA14-14-2 strain resulted in a lethal peripheral inflammatory response and organ damage without encephalitis in IFNAR mice. Our findings may help shed light on the peripheral immunopathogenesis associated with clinical JEV infection and aid in developing treatment options.
日本脑炎病毒（JEV）是全球蚊媒病毒性脑炎的主要病因。另一方面，除脑炎外的临床症状在JEV感染中更为普遍，这表明外周病理生理学具有相关性。我们在生物安全二级（BSL-2）条件下，使用感染SA14-14-2毒株的IFNAR缺陷（IFNAR）小鼠研究了JEV的外周免疫发病机制。感染IFNAR小鼠的体重和存活率显著下降。感染IFNAR小鼠的肝脏和脾脏表现出明显的组织损伤和炎性细胞浸润。器官中也存在广泛的病毒复制。外周组织和血清中IFN-α/β蛋白表达显著升高，尽管感染IFNAR动物的脾脏和肝脏中相关的干扰素刺激基因（ISG）仍然较低。同样，使用脾脏RNA测序进行的差异表达基因（DEG）分析显示炎性细胞因子上调，如IL-6、TNF-α和MCP-1，以及IFN-γ相关的细胞因子风暴。SA14-14-2感染的IFNAR小鼠的脾脏和肝脏中巨噬细胞和中性粒细胞的浸润显著增加。然而，脑组织损伤、病毒增殖或IFNα/β及炎性细胞因子的产生没有显著差异。JEV SA14-14-2毒株感染导致IFNAR小鼠出现致命的外周炎症反应和器官损伤，但无脑炎。我们的研究结果可能有助于阐明与临床JEV感染相关的外周免疫发病机制，并有助于开发治疗方案。
