Identifying Genetic Regulators and New Models of Wild Type Coronavirus Pathogenesis

摘要 SARS冠状病毒和最近的MERS冠状病毒是人类冠状病毒，从 人畜共患病人群感染并在人类中引起严重疾病。我们对此的理解 冠状病毒的发病机制在很大程度上限于在小动物模型中可以观察到的 似乎是对人类所见疾病的概括。SARS-CoV小鼠模型依赖于一种 与野生型人类分离株一样，小鼠适应株MA15可以在小鼠身上复制，但不能 引起明显的疾病征兆。复制模型也未能捕捉到 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疗法或疫苗。 功效。而小鼠适应的SARS-CoV感染概括了人类的许多方面 SARS冠状病毒病，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。通道模型存在以下风险 从自然宿主中发生的改变病毒的趋向性或复制，并需要测序 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研究暂停和获得期间受到限制 现在可能属于HHS P3CO框架，从而限制了我们快速识别疾病的能力 新出现病原体的模型。此外，一种产生疾病的通道方法 模型是耗时的，这在新病毒的背景下是负担不起的 疫情爆发。通过建立新的野生型SARS-CoV致病小鼠模型，我们将 为评估新发人畜共患病的致病潜力提供了重要工具 冠状病毒以及测试新疗法和疫苗的资源。此外，我们 将确定决定对野生型SARS-CoV的致病反应的基因调节器 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.