新冠病毒鼠适应株及其感染模型研究进展与展望

Progress and Perspective of SARS-CoV-2 Mouse-adapted Strains and the Mouse Models

新型冠状病毒(以下简称“新冠病毒”)肺炎疫情(以下简称“疫情”)暴发以来在全球范围内持续传播,截至目前全球已经有超过4.5亿人感染,并已造成超过600万人死亡。小动物感染模型是疫苗、药物研发及致病机制研究不可或缺的工具。然而,疫情早期的新冠病毒分离株无法感染标准实验小鼠,因而无法直接利用新冠病毒自然分离株建立基于标准实验小鼠的感染模型。为突破这一瓶颈,我们采用在小鼠体内强制连续传代的策略对新冠病毒进行适应驯化,最终获得了对标准实验小鼠具有不同感染和致病能力的鼠适应株,并以此系统性地建立了可模拟新冠肺炎轻度至重度症状的小鼠感染模型。我们通过深度测序、亲和能力分析及蛋白晶体结构解析等方法进一步探究了新冠病毒鼠适应分子机制。新冠病毒鼠适应株及感染模型的建立有效助力了多种新冠疫苗、药物的研发及新冠病毒致病机制研究,为新冠疫情的防控做出了重要贡献。本文从新冠病毒适应株的驯化、鼠适应性的结构与生物学基础、感染模型的建立及应用等方面系统回顾研究成果并对新冠病毒鼠适应株相关研究进展作一简要综述。

Since the outbreak of COVID-19,its causative agent,SARS-CoV-2,continues to transmit,which has caused more than 450 million cases and 6 million deaths.In order to prevent the spread of COVID-19,a variety of vaccines and drugs are being developed and the pathogenesis is also being studied.Small animal models are indispensable tools for these research work.However,SARS-CoV-2 clinical isolates in early stage of the pandemic cannot effectively infect standard laboratory mice,thus the infection models cannot be directly established with them.To overcome this barrier,we adopted the strategy of serially passaging SARS-CoV-2 in mice,and finally obtained mouse-adapted SARS-CoV-2 strains with different infectivity and pathogenicity to standard laboratory mice,and successfully established mouse infection models that can simulate mild to severe clinical characteristics of COVID-19.Furthermore,we explored the molecular mechanism of mouse adaptation of SARS-CoV-2 by deep sequencing,affinity and protein crystal structure analysis.The mouse-adapted strains and models we built provide an effective research platform for the evaluation of agents and the exploration of SARS-CoV-2 pathogenesis.In this paper,we reviewed the development of mouse-adapted SARS-CoV-2 and the structural and biological basis of mouse adaptation,as well as the establishment and application of mouse-adapted SARS-CoV-2 infection models.