hACE2转基因树鼩创制和SARS-CoV-2感染模型建立

新冠肺炎肆虐全球，对公众健康构成极大威胁。药物和疫苗研制是科技抗疫的焦点。是否有合适的动物模型用于药物和疫苗评价是关键瓶颈。树鼩是灵长类动物的近亲，能感染多种病毒，作为病毒感染性动物模型创建有一定的优势。申请人和团队成员一直从事树鼩免疫基因研究，阐明了其免疫遗传特性（PNAS 2016，J Immunol 2020）。前期申请人所在团队和合作者成功建立树鼩精原干细胞系，首次实现树鼩基因修饰的技术重大突破(Cell Res 2017)。这些工作为创建转基因树鼩病毒感染模型提供了坚实基础。申请人参与新冠科研攻关期间，发现树鼩能感染SARS-CoV-2，呈现部分新冠肺炎的临床症状，但病毒会被较快清除。本研究拟利用慢病毒和精原干细胞体系，建立过表达人源ACE2基因的转基因树鼩，探索建立SARS-CoV-2持续感染模型，明确转基因树鼩作为新冠肺炎研究的优势，更好的服务于新冠药物和疫苗的研发与评价工作

The pandemic of coronavirus disease 2019 (COVID-19) poses a global threat to the human population. Identifying animal species susceptible to infection with the pathogen SARS-CoV-2 / HCoV-19 is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. The Chinese tree shrew (Tupaia belangeri chinensis) is a close relative of primates. It can be infected by several viruses, including HBV, HCV, AIV and HSV-1. The tree shrew also possesses obvious advantages and potentials as a rising animal model for viral infections. In recent years, we have characterized the common and unique features of tree shrew immune genes, and showed the functional conservation and divergence of tree shrew immune system (PNAS 2016; J Immunol 2020). Together with collaborators, members of the applicant’s research team have successfully established the first genetic modification platform for the Chinese tree shrew using its spermatogonial stem cells (Cell Res 2017). All these studies have laid a solid basis for us to generate genetically modified tree shrews for studying viral infectious diseases. During the past months, along with colleagues, I have been fighting against the SARS-CoV-2. We found that the tree shrews can be infected by SARS-CoV-2 and the ACE2 viral entry receptor was essential during the SARS-CoV-2 infection. The infected animals present partial symptoms of COVID-19 and the viral shedding is not very high. Therefore, in this study, we plan to use the lentiviral expression vector to generate a transgenic tree shrew overexpressing human ACE2 protein. We will further characterize the SARS-CoV-2 infection of the hACE2 transgenic tree shrews and try to make a better infection model of COVID-19. We believe that this transgenic tree shrew model has the potential for evaluating drugs and vaccines for curing and preventing SARS-CoV-2 infection.