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

描述(申请人提供)：中东呼吸综合征冠状病毒(MERS-CoV)感染的暴发对全球公共卫生构成威胁。尽管预测的MERS大流行潜力仍然很低，但由于MERS-CoV在性质上的进一步演变，人与人之间传播的可持续性增加令人担忧。到目前为止，对这种新出现的人类疾病的发病机制和有效的干预措施都还不清楚，这在很大程度上是由于缺乏动物物种，特别是能够概括临床疾病对感染做出反应的小实验室物种。了解MERS冠状病毒在合适的动物模型中致病的机制有助于确定有效治疗方法的新靶点。虽然非人灵长类(NHP)(即恒河猴)对MERS冠状病毒是允许的，但NHP的感染导致急性但自我解决的呼吸应激的开始，没有任何死亡。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，使得这种模式不那么有吸引力，特别是在测试疫苗和疗法方面。动物模型的开发最近被NIH/NIAID列为MERS冠状病毒研究的优先领域。我们的实验室此前曾报道，对与SARS-CoV感染相关的临床疾病具有遗传抵抗力的小鼠在表达人ACE2病毒受体时，对病毒完全许可，导致发病率和死亡率。在前期工作的基础上，我们建议建立表达人CD26/DPPIV(HCD26)病毒受体的转基因小鼠，作为MERS冠状病毒的小动物模型。由于hCD26的表达并不局限于肺部，在本应用中，我们将产生具有hCD26组成性(Aim 1)或肺特异性表达(Aim 2)的转基因小鼠系，作为现有NHP模型的替代。这些转基因小鼠模型的成功建立不仅将有助于研究人类的发病率、死亡率和病毒复制，而且还将有助于评估针对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.