基于hACE2-KI小鼠模型的新型冠状病毒致病机理以及抗体交叉保护研究

新型冠状病毒引发的肺炎疫情（COVID-19）已造成400多万人感染，超29万人死亡，给世界各国的人民健康和经济发展带来沉重打击。本课题组自疫情暴发就参与了新冠病毒的分离和鉴定，并证实了新冠病毒可以用人血管紧张素转化酶2（ACE2）为细胞受体，但不能利用小鼠ACE2。新冠病毒全基因组分析表明其同穿山甲和蝙蝠的冠状病毒相似度为85-96%，位于同一进化分支。新冠疫情可能长期存在，且无症状感染者和长期携带者随时可能引起疫情暴发。只有深入了解新冠病毒的致病机理才有可能有效治疗新冠病人，从而控制疫情。因此本项目将基于hACE2原位敲入的小鼠模型，比较穿山甲冠状病毒和新冠病毒的在受体利用，复制能力、致病力的异同，通过比较病原学，阐明新冠病毒的致病机理，鉴定新冠病毒的毒力因子和机制；同时评价不同冠状病毒的血清学和交叉保护效果。项目完成将为新冠病毒致病机理以及疾病的治疗和防控提供理论基础和技术支持。

The novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 4 million infections and about 290,000 patient deaths. The pandemic of COVID-19 shadowed a severe affect to the public health and economic development around the world. Our laboratory had been involved the work of virus isolation, genome sequencing and animal model infection since the outbreak. We successfully isolated the virus and confirmed that SARS-CoV-2 could use human angiotensin converting enzyme 2 (ACE2) as a cell receptor, but not the mouse ACE2. The genome analysis of SARS-CoV-2 showed that it shared 85-96% similarity with pangolin and bat coronaviruses, and located in the same branch of the phylogenetic tree. The COVID-19 epidemic may exist for a long time, and asymptomatic infections and long-term carriers may cause outbreaks at any time. Understanding of the pathogenic mechanism of SARS-CoV-2 is the key factor to treat patients effectively and control the epidemic. Therefore, this project will compare the similarities and differences of receptor utilization, replication capacity and pathogenicity of pangolin coronavirus and SARS-CoV-2 based on the in situ hACE2 knock-in mouse model. Through the comparison of similarities and differences of these two coronaviruses, we want to clarify the pathological mechanism of SARS-CoV-2, and identify the key virulence factors; meanwhile, we also will evaluate the serological and cross-protective effects of different coronaviruses. The completion of the project will provide theory and technical support for the pathology mechanism of SARS-CoV-2 and the therapeutic and prevention of COVID-19.