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人类病毒研究长期受限于物种特异性差异，传统小鼠模型难以复现病毒自然感染过程。本文系统梳理了近年基于基因编辑与人类免疫系统重建技术构建的系列转基因小鼠模型，包括关键免疫基因敲除、病原体受体敲入、人源化MHC转基因及人免疫系统重建小鼠，这些模型显著提升了小鼠对严重急性呼吸道综合征冠状病毒2型（Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2）、登革病毒（Dengue virus, DENV）、肠道病毒71型（Enterovirus 71, EV71）、人类免疫缺陷病毒1型（Human immunodeficiency virus type 1, HIV-1）等人类病毒的易感性，并在病毒入侵机制、免疫应答规律、疫苗及药物评价中发挥了关键作用。此外，文章还客观分析了当前模型在模拟免疫系统完整性、受体表达水平、免疫细胞功能、稳定性以及长期适用性等方面存在的局限性，提出整合基因编辑技术、异体移植技术、多组学以及类器官技术以进一步优化模型的未来发展方向。
Abstract：Research on human viruses has long been limited by species-specific barriers, as conventional mouse models often fail to faithfully recapitulate the natural infection processes of human pathogens. This review systematically summarizes recent advances in transgenic mouse models developed through gene-editing and human immune system reconstitution technologies, including mice with targeted immune gene knockouts, pathogen receptor knock-ins, humanized MHC transgenes, and human immune system reconstitution. These models have markedly improved the susceptibility of mice to human viruses such as Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2), Dengue virus(DENV), Enterovirus 71(EV71), and Human immunodeficiency virus type 1(HIV-1), They have become in dispensable tools for elucidating viral entry mechanisms, characterizing immune response dynamics, and assessing vaccine and antiviral efficacy. Furthermore, this article critically discusses the limitations of current models in replicating the full integrity of the human immune system, including constraints related to receptor expression, immune cell functionality, stability, and long-term applicability. Finally, it proposes future directions for optimizing these models through the integration of gene-editing technologies, allogeneic transplantation, multi-omics approaches, and organoid systems, aiming to further enhance their translational relevance in human virology research.
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基本信息:
DOI：10.13242/j.cnki.bingduxuebao.250236
中图分类号:R373
引用信息:
[1]李熙平,王馨茹,岳磊,等.病毒诱导人类疾病研究中转基因小鼠的发展与应用[J].病毒学报,2026,42(01):304-313.DOI:10.13242/j.cnki.bingduxuebao.250236.
基金信息:
中国医学科学院医学与健康科技创新工程项目（项目号：2021-1-I2M-043）,题目：创新疫苗关键技术研究; 云南省科技人才与平台计划（项目号：202105AC160025）,题目：中青年学术和技术带头人后备人才项目; 云南省重大科技专项计划（项目号：202302AA310004）,题目：利用新型易感模型开展CV-A6、CVA10联合病毒样颗粒疫苗临床前预研究~~
2025-08-04
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2025-12-18
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