Human ACE2 transgenic pigs: A large animal model for Covid-19

准确反映新冠肺炎病的动物模型将是疫苗开发、抗病毒测试和发病机制研究的关键。活体研究的成功应用将取决于多种动物模型方法的结合。研究新冠肺炎的动物模型有很多。啮齿动物模型，包括老龄小鼠、表达hACE2的转基因小鼠和感染小鼠适应病毒的小鼠，都已被使用。金色叙利亚仓鼠也容易感染人类冠状病毒。雪貂对感染很敏感，并已显示出作为病毒传播模式的前景。非人灵长类动物是与人类感染最相似的模型。虽然这些模式都有优点，但也有缺点。啮齿动物模型不能准确反映人类疾病，它们的大体形态和免疫反应与人类不同。雪貂缺乏分子工具，而非人类灵长类动物价格昂贵，仅限于世界上的几个机构。越来越多的人认识到使用牲畜物种作为人类疾病的模型。我们建议发展猪作为新冠肺炎的大型动物模型。与非人类灵长类动物相比，它们的使用限制较少，相关的分子工具正在迅速改进。由于猪对SARS-CoV-2不敏感，我们将培育表达人血管紧张素转换酶2(ACE2)的转基因猪。ACE2是SARS-CoV-2的主要受体，也是物种易感性的主要决定因素。新冠肺炎不仅是疫苗开发和抗病毒测试的优秀模型，而且对于回答病毒发病机制的重要问题也是极其有价值的，例如：哪些细胞、组织和器官被感染以及何时被感染？病毒是如何在体内传播的？病毒会感染中枢神经系统吗？心血管疾病的长期后果是什么？哪些因素会影响宿主之间的传播？这些研究不仅对我们成功应对当前大流行的能力至关重要，而且对我们应对未来大流行的能力也很重要。

Animal models which accurately reflect Covid-19 disease will be critical for vaccine development, antiviral testing and pathogenesis studies. Successful application of in vivo studies will depend on a combination of approaches from multiple animal models. There are a number of animal models for studying Covid-19. Rodent models, including aged mice, mice engineered to express hACE2 and mice infected with mouse adapted virus, have all been used. Golden Syrian hamsters are also susceptible to human coronaviruses. Ferrets are susceptible to infection and have shown promise as models of viral spread. Non-human primates are the most comparable model to human infections. While each of these models has advantages, there are also drawbacks. Rodent models do not accurately reflect human disease and their gross morphology and immunological responses are divergent from humans. Ferrets lack molecular tools, while non-human primates are expensive and restricted to a few institutions around the world. There is a growing appreciation of the use of livestock species as models for human disease. We propose developing pigs as large animal models for Covid-19. Their use is less restrictive compared to non-human primates and associated molecular tools are improving rapidly. As pigs are not susceptible to SARS-CoV-2, we will generate transgenic pigs that express the human angiotensin-converting enzyme 2 (ACE2), the main receptor for SARS-CoV-2 and main determinant of species susceptibility. As well as being an excellent model for vaccine development and antiviral testing, a viable pig model of Covid-19 would be extremely valuable to answer important questions of viral pathogenesis such as; which cells, tissues and organs are infected and when? How does the virus spread within the body? Does the virus infect the central nervous system and what are the long-term consequences of cardiovascular involvement? What factors effect spread between hosts?These studies will not only be critical in our ability to successfully respond to the current pandemic, but will be important for our ability to respond to future pandemics.