Identifying Genetic Regulators and New Models of Wild Type Coronavirus Pathogenesis

摘要 SARS-CoV和最近的MERS-CoV是人类冠状病毒， 人畜共患病人群感染并导致人类严重疾病。我们理解 冠状病毒的发病机制主要限于在小动物模型中观察到的， 似乎重现了在人类身上发现的疾病。SARS-CoV小鼠模型依赖于 小鼠适应的病毒株MA 15与野生型人分离株一样在小鼠中复制，但不 引起明显的疾病迹象。复制模型也无法捕捉 人类对感染的反应-呼吸功能障碍、炎症和其他疾病迹象。 因此，复制模型不能用于评估抗病毒治疗或疫苗 功效虽然小鼠适应的SARS-CoV感染重现了人类的许多方面， 在SARS-CoV疾病中，该病毒有六个点突变，分散在整个基因组中， 直到SARS疫情结束后的几年才产生。传代模型有可能 改变病毒的嗜性或复制，使其不同于天然宿主，并需要测序 和广泛的分析知道每个突变的位置和影响。重要的是冠状病毒 通道实验最近在功能获得研究暂停期间受到限制， 现在可能属于HHS P3 CO框架，从而限制了我们快速识别疾病的能力 新型病原体的模型。此外，通过一种方法来产生一种疾病 模型是耗时的，这是在一种新病毒的背景下无法承受的 爆发通过建立一种新的野生型SARS-CoV发病机制的小鼠模型，我们将 为评估新出现的人畜共患病的致病潜力提供了重要工具 冠状病毒以及用于测试新疗法和疫苗的资源。另外我们 将确定决定对野生型SARS-CoV的致病反应的遗传调节因子 感染

ABSTRACT SARS-CoV, and more recently MERS-CoV, are human coronaviruses that have emerged from zoonotic populations to infect and cause severe disease in humans. Our understanding of coronavirus pathogenesis is largely limited to what can be observed in small animal models which appear to recapitulate the disease seen in humans. The SARS-CoV mouse model relies on a mouse adapted strain of virus, MA15, as the wild type human isolates replicate in mice but do not cause appreciable signs of disease. Replication models also fail to capture key aspects of the human response to infection – respiratory dysfunction, inflammation and other signs of disease. As such, replication models cannot be used to assess either antiviral therapeutics or vaccine efficacy. While mouse adapted SARS-CoV infection recapitulates many of the aspects of human SARS-CoV disease, the virus has six point mutations scattered throughout the genome and was not generated until years after the end of the SARS epidemic. Passage models run the risk of altering virus tropism or replication from what occurs in the natural host and require sequencing and extensive analysis know the location and effect of each mutation. Importantly, coronavirus passage experiments were recently restricted during the Gain of Function research pause and could now fall under the HHS P3CO Framework, thus limiting our ability to rapidly identify disease models for emerging pathogens. Additionally, a passage approach to generating a disease models is time consuming, something that cannot be afforded in the context of a novel virus outbreak. By generating a new mouse model of wild type SARS-CoV pathogenesis we will provide an important tool for the evaluation of the pathogenic potential of emerging zoonotic coronaviruses as well as a resource for testing novel therapeutics and vaccines. Additionally we will identify genetic regulators that dictate a pathogenic response to wild type SARS-CoV infection.