Establishment of a Transgenic Mouse Model for Middle East Respiratory Syndrome Co

描述（由申请人提供）：中东呼吸综合征冠状病毒（MERS-CoV）感染的爆发对全球公共卫生构成威胁。尽管预计中东呼吸综合征大流行的可能性仍然很低，但令人关切的是，由于中东呼吸综合征冠状病毒在性质上的进一步演变，人与人之间传播的可持续性有所增加。迄今为止，这种新出现的人类疾病的发病机制和有效干预措施都还不清楚，这主要是由于缺乏动物物种，特别是缺乏能够在感染反应中重现临床疾病的小型实验室物种。了解MERS-CoV在合适的动物模型中引起疾病的机制有助于确定开发有效治疗方法的新靶点。虽然非人类灵长类动物（即恒河猴）易受中东呼吸综合征冠状病毒感染，但非人类灵长类动物的感染会导致急性但可自行消退的呼吸压力发作，而不会导致死亡。此外，高昂的成本、不同程度的组织病理学以及短暂和有限的临床疾病的性质使这种模式不那么有吸引力，特别是用于测试疫苗和治疗方法。动物模型的开发最近被NIH/NIAID列为中东呼吸综合征冠状病毒研究的优先领域。我们的实验室以前报道过，对SARS-CoV感染相关临床疾病具有遗传抗性的小鼠在表达人类ACE2病毒受体时，对该病毒完全允许，导致发病率和死亡率。基于我们之前的成功，我们提出建立表达人CD26/DPPIV （hCD26）病毒受体的转基因小鼠作为MERS-CoV的小动物模型。由于hCD26的表达并不局限于肺部，我们将在本应用中产生具有hCD26组成表达（Aim 1）或肺特异性表达（Aim 2）的转基因小鼠谱系，作为现有NHP模型的替代方案。这些转基因小鼠模型的成功建立不仅有助于研究人类的发病率、死亡率和病毒复制，而且有助于评估针对MERS-CoV开发的预防和治疗药物。

DESCRIPTION (provided by applicant): The outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infections poses a threat to public health worldwide. Although the predicted pandemic potential of MERS remains low, an increase in the sustainability of human-to-human transmission, as a result of further evolution of MERS-CoV in nature, is of concern. To date, neither the pathogenesis nor effective intervention against this newly emerged human disease is available, largely due to the lack of animal species, especially, the small laboratory species that can recapitulate clinical illness in response to infection. Understanding the mechanism used by MERS-CoV to cause diseases in suitable animal models can help in identifying novel targets for the development of effective therapeutics. While nonhuman primates (NHP) (i.e., rhesus macaques) are permissive to MERS-CoV, the infection in NHPs results in the onset of acute, but self-resolving, respiratory stress without any mortality. Moreover, the high cost, varying degrees of histopathology, and the nature of transient and limited clinical illness make this model less attractive, especially for testing vaccines and therapeutics. Development of animal models has recently been listed as a prioritized area of MERS-CoV research by NIH/NIAID. Our laboratory has previously reported that mice which are inheritably resistant to clinical illness associated with SARS-CoV infection became fully permissive to the virus, resulting in morbidity and mortality, when expressing human ACE2 viral receptor. Based on our prior success, we propose establishing transgenic mice expressing the human CD26/DPPIV (hCD26) viral receptor as the small animal model for MERS-CoV. As the expression of hCD26 is not restricted to the lungs, we will generate transgenic mouse lineages with either constitutive (Aim 1) or lung-specific expression of hCD26 (Aim 2) in this application, as an alternative to the existing NHP model. Successful establishment of these transgenic mouse models will be useful not only for studying morbidity, mortality, and viral replication in humans, but also for evaluating preventive and therapeutic agents developed against MERS-CoV.