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Adv Sci | 南京大学李颜,广州医科大学赵金存:新型肺-免疫系统双人源化小鼠模型用于低冠病毒感染与免疫研究

  • 2026-04-17 13:48:42
Adv Sci | 南京大学李颜,广州医科大学赵金存:新型肺-免疫系统双人源化小鼠模型用于低冠病毒感染与免疫研究

研究背景：

人源化小鼠模型是指在小鼠体内携带人类基因、细胞或组织，从而具备更接近人类生理环境与疾病特征的实验动物体系，已广泛应用于疾病机制研究、精准药物开发、临床诊疗优化和传染病防控等领域。其中，通过将人胎肺组织植入免疫缺陷小鼠体内构建的肺人源化小鼠，能够在体内重建人肺样结构，从而模拟人类呼吸道病毒感染，解决许多人源呼吸道病毒无法在传统小鼠体系中感染的难题。然而，该模型长期依赖新鲜人胎肺组织，不仅来源受限，也难以实现体系标准化和规模化应用，显著限制了其科研应用与临床前转化潜力。

21世纪以来，SARS、MERS以及COVID-19三次全球流行凸显了冠状病毒研究的重要性。除这些高致病性冠状病毒外，人低致病性冠状病毒（CCCoVs，包括229E、NL63、OC43和HKU1）在全球人群中普遍流行，多引起轻至中度呼吸道症状，并在致病性、组织嗜性及免疫反应等方面与高致病性冠状病毒存在显著差异，对理解冠状病毒演化、宿主适应和潜在免疫交叉具有重要意义。然而，受感染史复杂、临床样本获取困难以及病毒高度宿主特异性等限制，CCCoVs，尤其是HKU1的体内感染研究体系长期缺乏。

文章概述：

南京大学李颜课题组与广州医科大学赵金存课题组通过系统优化冻存人胎肺组织的移植策略，首次构建了能够稳定支持多种CCCoVs感染的肺-免疫系统双人源化小鼠模型，并解析了人肺组织的免疫微环境及其在病毒感染后的免疫应答特征。该成果不仅突破了HKU1体内感染模型长期缺失的瓶颈，也为呼吸道病毒感染、免疫机制研究及抗病毒药物评价提供了新的实验平台。相关研究发表于Advanced Science。

图文导读：

研究人员通过补充生长因子并系统评估冻存组织块大小与数量，显著提升了冻存人胎肺组织的重建效率，构建结构成熟、细胞组成完整的人肺样组织。在此基础上分别构建四种CCCoVs及SARS-CoV-2感染模型，并显示其在复制动力学、靶细胞谱与组织损伤方面均存在显著差异，同时在HKU1模型中验证Paxlovid的抗病毒效果。该体系为比较不同冠状病毒的致病机制及开展药物评估提供了可操作的体内研究框架。

在前述移植体系的基础上，研究人员通过联合移植人胎肺组织和造血干细胞，构建了新型的肺-免疫系统双人源化小鼠模型。流式与单细胞转录组测序结果显示，与鼠肺相比，人肺组织能够更有效支持人免疫细胞定植和成熟，显著富集人组织驻留记忆T细胞与人巨噬细胞，提示肺组织微环境对人免疫系统重建具有关键作用。值得注意的是，尽管大量未感染SARS-CoV-2的人群中可检测到针对其的反应性T细胞，但其来源一直缺乏直接实验证据。研究人员首次利用双人源化小鼠进行HKU1感染，发现可诱导病毒特异性T细胞应答并伴随低水平SARS-CoV-2交叉反应，为CCCoVs与SARS-CoV-2之间可能存在的免疫关联提供了直接证据。

图1

南京大学博士研究生程春雨、广州医科大学孙静教授以及南京大学硕士研究生卢纯、余倩为论文的共同第一作者。南京大学李颜教授、广州医科大学赵金存教授以及南京鼓楼医院丁帅研究员为共同通讯作者。

论文信息

A Lung-Immune Dual-Humanized Mouse Using Cryopreserved Tissue Enables Infection and Immune Profiling of Human Common Cold Coronaviruses

Chunyu Cheng, Jing Sun, Chun Lu, Qian Yu, Yiyun He, Bingqing Wu, Deshan Ren, Shuai Ding*, Jincun Zhao*, Yan Li*

Advanced Science 

DOI:10.1002/advs.202512097

原文链接

https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202512097

李颜实验室招聘信息

李颜，南京大学教授/昌平实验室科学家，致力于免疫系统人源化小鼠模型的构建与应用，填补了国内在人源化小鼠模型方面的空白，并将其用于推动生命科学与生物医药产业的发展，以通讯作者（含共通讯）在Cell, Cancer Cell x 2, Cell Research, Nature Cancer, Science Advances，Advanced Science等重要期刊中发表多篇论文，并转化多项专利授权。李颜课题组以免疫系统人源化小鼠为核心工具，致力于以下四个方向的研究：1.免疫系统全人源化小鼠模型研发；2.传染病/肿瘤/自免药物人体作用机制；3.人特异性免疫治疗靶点发现；4.基于人源化小鼠获取全人抗体与TCR-T药物。现根据工作规划，课题组在昌平实验室招聘多名肿瘤免疫治疗方向的博士后研究人员，有意者可将简历发送至yanli@nju.edu.cn，并抄送baijian@cpl.ac.cn。

相关链接：https://mp.weixin.qq.com/s/xvnd7bPDCfwxLOKE-Szvpw

期刊简介

Advanced Science是 Wiley旗舰期刊 Advanced 系列中的一种完全开放获取的跨学科科学期刊，发表材料科学、物理、化学、医学、生命科学、环境科学、工程和社会科学等领域的前沿基础和应用研究。我们的使命是通过开放获取出版，使前沿创新的科学研究具有更广泛的可访问性。Wiley 的 Advanced 系列是全球公认的高影响力期刊系列，传播来自资深和青年研究人员的科学成果，帮助他们实现使命并扩大科学发现的影响力。

Advanced Science最新2024影响因子（JIF）为 14.1，五年平均影响因子为 15.6，JCI 引文指标为1.90，CiteScore 为 18.2。在 2025年中国科学院院文献情报中心期刊分区表中，Advanced Science入选综合类期刊一区TOP。

本文来自网友投稿或网络内容，如有侵犯您的权益请联系我们删除，联系邮箱：wyl860211@qq.com 。

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  1. CONNECT:[ UseTime:0.001104s ] mysql:host=127.0.0.1;port=3306;dbname=b460;charset=utf8mb4
  2. SHOW FULL COLUMNS FROM `fenlei` [ RunTime:0.001631s ]
  3. SELECT * FROM `fenlei` WHERE `fid` = 0 [ RunTime:0.001757s ]
  4. SELECT * FROM `fenlei` WHERE `fid` = 63 [ RunTime:0.000769s ]
  5. SHOW FULL COLUMNS FROM `set` [ RunTime:0.001357s ]
  6. SELECT * FROM `set` [ RunTime:0.000559s ]
  7. SHOW FULL COLUMNS FROM `article` [ RunTime:0.001455s ]
  8. SELECT * FROM `article` WHERE `id` = 499048 LIMIT 1 [ RunTime:0.001130s ]
  9. UPDATE `article` SET `lasttime` = 1776566454 WHERE `id` = 499048 [ RunTime:0.005071s ]
  10. SELECT * FROM `fenlei` WHERE `id` = 65 LIMIT 1 [ RunTime:0.000617s ]
  11. SELECT * FROM `article` WHERE `id` < 499048 ORDER BY `id` DESC LIMIT 1 [ RunTime:0.001715s ]
  12. SELECT * FROM `article` WHERE `id` > 499048 ORDER BY `id` ASC LIMIT 1 [ RunTime:0.001160s ]
  13. SELECT * FROM `article` WHERE `id` < 499048 ORDER BY `id` DESC LIMIT 10 [ RunTime:0.004318s ]
  14. SELECT * FROM `article` WHERE `id` < 499048 ORDER BY `id` DESC LIMIT 10,10 [ RunTime:0.003069s ]
  15. SELECT * FROM `article` WHERE `id` < 499048 ORDER BY `id` DESC LIMIT 20,10 [ RunTime:0.001997s ]
0.207909s