IL2rg - / - 大鼠支持人 RSV 在体内的长期感染
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1. 中国食品药品检定研究院实验动物资源研究所(国家啮齿类实验动物资源库),北京 102629;2. 北京大学 医学部基础医学院病原生物学系,北京 100083;3. 中国食品药品检定研究院安全评价研究所(国家药物安全 评价监测中心),北京 100176

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R-33

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IL2rg - / -rats support prolonged infection of human RSV
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1.Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, National Rodent Laboratory Animal Resources Center, Beijing 102629, China; 2. Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100083, China; 3. National Center for Safety Evaluation of Drugs, Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing 100176, China

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    摘要:

    目的 为了克服已有人呼吸道合胞病毒( human respiratory syncytial virus,hRSV)动物模型的局限性,如半受纳性和感染持续时间短,本文利用 TALEN 基因编辑技术建立了 IL2rg 基因敲除( IL2rg- / -)的大鼠模型。 方法 用 hRSV 滴鼻感染该动物模型,观察感染期(0 ~ 35 d)的临床表征、体重及体温变化;记录不同时间点(滴鼻感染后第 4、11、20、35 天)鼻腔、气管、肺等呼吸道脏器的病毒总拷贝数;在观察终点(滴鼻感染后第 35 天)对感染动物的靶器官进行病理分析;观察不同时间点(滴鼻感染后第 4、20、35 天)外周血 T、B、NK、NKT 细胞的变化及不同时间点多种细胞因子的变化。 结果 (1)通过鼻内接种 hRSV 后,纯合的 IL2rg 基因敲除大鼠的呼吸道内能保持较高的病毒载量,鼻腔中病毒的平均峰值滴度能快速升至 1 × 1010 copies/ g,至第 5 周时,病毒依然能维持复制,病毒载量亦可达到 1 × 107 copies/ g。 (2)但其鼻、气管和肺组织,无明显病变。 (3)感染 hRSV 的 IL2rg- / -大鼠外周血B 细胞含量有上升。 (4)IL-6 和 MCP-1 两种细胞因子都在感染前期上升,在观察终点回落。 结论 本研究基于TALEN 技术建立了 IL2rg- / -大鼠模型,并发现该模型能很好地支持 hRSV 高水平复制和并长期感染,为抗病毒药物筛选、抗 hRSV 抗体体内效力评价,提供了良好的动物模型。

    Abstract:

    Objective To overcome the limitations of existing human respiratory syncytial virus ( hRSV) animal models, such as semi-permissiveness and short duration of infection, this study established an IL2rg gene knockout (IL2rg- / -) rat model using TALEN gene editing technology. Methods The animal model was infected with hRSV intranasally. Clinical characteristics, body weight, and temperature changes were observed over the infection period(0 ~35 days). The total viral loads in respiratory organs, such as the nasal tissue, trachea, and lungs, were measured at various time points (4, 11, 20, and 35 days post-infection). Pathological analysis was conducted on target organs at the endpoint of observation ( 35 days post-infection). Changes in peripheral blood T, B, NK, and NKT cells and various cytokines were assessed at various time points(4, 20, and 35 days post-infection). Results (1) IL2rg- / - knockout rats sustained high viral loads in the nasal cavity upon intranasal inoculation with hRSV. The average peak titer rapidly reached 1 × 1010 copies/ g in nasal tissue and 1 × 107 copies/ g up to 5 weeks post-infection. ( 2) However, no significant pathological changes were noted in nasal, tracheal, or lung tissues. ( 3) An increase was observed in the content of peripheral blood B cells in hRSV-infected IL2rg - / - rats. (4) IL-6 and MCP-1 were increased in the early stage of infection and then decreased at the end of the observation period. Conclusions This study established a new IL2rg - / -rat model using TALEN technology and found that this model effectively supported high-level replication and long-term infection of hRSV, providing a good basis for antiviral drug screening and in vivo efficacy evaluation of anti-hRSV antibodies.

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熊芮,吴勇,杨艳伟,屈哲,刘甦苏,王誉雅,马丽颖,付瑞,彭宜红,梁春南,范昌发. IL2rg - / - 大鼠支持人 RSV 在体内的长期感染[J].中国比较医学杂志,2024,34(01):17~24.

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  • 收稿日期:2023-07-06
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  • 在线发布日期: 2024-03-04
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自2024年1期开始,杂志参考文献改为中英文对照,具体格式要求可置下载中心查看!
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