The slow progression of Japanese encephalitis in aged mice is likely associated to B cell recruitment in the brain

Zheng-Ran Song; Yi-Lin Yang; Yang Zhou; Li-Bo Liu; Fei-Yang Xue; Lin-Shen-Yang Liu; Na Gao; Dong-Ying Fan; Yi-Song Wang; Jing An; Pei-Gang Wang

doi:10.1016/j.virs.2025.05.013

August 2025

. doi: 10.1016/j.virs.2025.05.013

Citation: Zheng-Ran Song, Yi-Lin Yang, Yang Zhou, Li-Bo Liu, Fei-Yang Xue, Lin-Shen-Yang Liu, Na Gao, Dong-Ying Fan, Yi-Song Wang, Jing An, Pei-Gang Wang. The slow progression of Japanese encephalitis in aged mice is likely associated to B cell recruitment in the brain .VIROLOGICA SINICA, 2025, 40(4) : 546-559. http://dx.doi.org/10.1016/j.virs.2025.05.013

老年小鼠乙脑进展缓慢可能与脑内募集的B细胞有关

宋正然 ^a,c ,
杨祎林 ^a,c ,
周杨 ^a,c ,
刘利波 ^b ,
薛飞飏 ^a,c ,
刘林申阳 ^a,c ,
范东瀛 ^a,c ,
高娜 ^a,c ,
王一松 ^a,c,, ,
安静 ^a,c,, ,
王培刚 ^a,c,,

a 首都医科大学基础医学院;
b 贵州医科大学基础医学院;
c 首都医科大学基础临床联合实验室

通讯作者： 王一松, yswang@ccmu.edu.cn; 安静, anjing@ccmu.edu.cn; 王培刚, pgwang@ccmu.edu.cn
收稿日期： 2024-12-31
录用日期： 2025-05-30

摘要

日本脑炎病毒 (JEV) 是引起流行性乙型脑炎 (JE) 的病原体，主要感染儿童，引起严重的中枢神经系统疾病。近年来虽然乙脑疫苗在儿童群体中的普遍接种，然而老年患者比例显著增加。但针对老年人JEV感染的研究仍然有限。为探究老年小鼠感染乙脑病毒后的病理特点及发病机制，我们建立了老年小鼠与年轻小鼠的JEV感染模型，并评估了两年龄组小鼠脑组织的病理改变与脑内主要细胞类型的感染情况。此外，我们对两年龄组小鼠感染乙脑病毒后的脑组织进行了转录组测序，以描述感染乙脑病毒后的免疫水平变化。相较于年轻小鼠，老年小鼠感染乙脑病毒后死亡率低，疾病进展较慢，脑组织病变轻。而两年龄组小鼠的脑组织病毒载量与脑内主要细胞的感染情况是相同的。转录组测序结果表明老年小鼠免疫水平较低，脑内炎症反应较轻。此外，老年小鼠脑内小胶质细胞活化能力较弱，CD8+ T 细胞功能较低。重要的是，乙脑病毒感染后，老年小鼠脑组织特异性招募大量B细胞。最后，相关性分析提示这群B细胞可能与CD8+ T细胞在乙脑进展中发挥着相反的作用。相较于年轻小鼠，老年小鼠对乙脑进展更加耐受，脑组织病变较弱。这种耐受与病毒的感染差异无关，而是由老年小鼠脑内低水平的免疫反应导致的。其中，老年小鼠脑内特异性募集的B细胞可能在抑制乙脑进展中发挥关键作用。
- 日本脑炎病毒
- , 老年小鼠
- , 转录组测序
- , 炎症
- , B细胞

The slow progression of Japanese encephalitis in aged mice is likely associated to B cell recruitment in the brain

Zheng-Ran Song ^a,c ,
Yi-Lin Yang ^a,c ,
Yang Zhou ^a,c ,
Li-Bo Liu ^b ,
Fei-Yang Xue ^a,c ,
Lin-Shen-Yang Liu ^a,c ,
Na Gao ^a,c ,
Dong-Ying Fan ^a,c ,
Yi-Song Wang ^a,c,, ,
Jing An ^a,c,, ,
Pei-Gang Wang ^a,c,,

a. Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China;
b. Department of Parasitology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 561113, China;
c. Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China

Corresponding author: Yi-Song Wang, yswang@ccmu.edu.cn Jing An, anjing@ccmu.edu.cn Pei-Gang Wang, pgwang@ccmu.edu.cn
Received Date: 31 December 2024
Accepted Date: 30 May 2025

Abstract

The Japanese encephalitis virus (JEV) causes Japanese encephalitis (JE), a severe disease that primarily affects children and induces significant central nervous system complications. With the widespread adoption of vaccination in children, the incidence among older individuals has increased substantially. Despite this epidemiological shift, research on JEV infection in the elderly remains limited. We established JEV infection models using both aged and young mice to explore age-related differences in pathology and underlying mechanisms. Brain tissue samples were analyzed for pathological changes and viral tropism in major cell types. To further characterize immune response variations, we conducted transcriptomic sequencing on the brain tissues following JEV infection. Aged mice exhibited lower mortality, delayed disease progression, and milder brain pathology compared to young mice after JEV infection. Viral titers and infection rates of major brain cell types were similar in both groups. Transcriptomic analysis revealed diminished immune activation and weaker inflammatory responses in aged mice. Additionally, microglial activation and CD8⁺ T cell function were significantly reduced. Interestingly, JEV infection induced the selective recruitment of B cells in the brains of aged mice. These B cells may modulate the effects of CD8⁺ T cells in the disease process. Compared to young mice, aged mice showed enhanced resistance to JEV progression and reduced brain pathology. This resistance was associated with a weakened immune response in the aged brain, rather than differences in viral infection. The specific recruitment of B cells in the brains of aged mice may play a crucial role in limiting disease progression.
- Japanese encephalitis virus (JEV)
- , Aged mice
- , RNA-seq
- , Inflammation
- , B cells

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