Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing 100050, China.
Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China.
Viruses. 2018 Aug 23;10(9):448. doi: 10.3390/v10090448.
Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.
中东呼吸综合征冠状病毒（MERS-CoV）感染会导致呼吸道疾病，且死亡率较高（~35%）。由于该病毒需要在生物安全三级（BSL-3）设施中进行操作，这阻碍了急需的抗病毒药物的研发。在这里，我们通过使用 CRISPR/Cas9 将人二肽基肽酶 4（hDPP4）插入 Rosa26 基因座，在一个遗传稳定的小鼠品系中实现了转基因的全局表达，从而建立了一种新型的小鼠模型。这些小鼠对 MERS-CoV 临床株 hCoV-EMC 非常易感，会导致动物出现严重的弥漫性肺部疾病，并且还可以被优化的假型 MERS-CoV 感染。中和单克隆抗体 H111-1 和 m336 以及融合抑制剂肽 HR2P-M2 的给药可以保护小鼠免受真实和假型 MERS-CoV 的攻击。这些结果证实，hDPP4 敲入小鼠是研究 MERS-CoV 发病机制和在 BSL-3 和 BSL-2 设施中抗 MERS-CoV 抗病毒药物的新型模型。
