人ACE2转基因小鼠对SARS-CoV的易感性

Susceptibility of hACE2 Transgenic ICR Mice to SARS-CoV Infection

目的建立敏感的SARS小动物模型。方法通过显微注射技术,将编码SARS-CoV细胞受体的人血管紧张素转换酶(hACE2)基因导入小鼠的基因组中制备了hACE2转基因小鼠,在小鼠ACE2(mACE2)启动子的调控下,hACE2蛋白在转基因小鼠的肺脏、心脏、肾脏和小肠表达。我们观察了野生型和转基因小鼠在SARS冠状病毒接种后病原学和病理学方面的反应。结果在接种后第3天和第7天,病毒能够更有效地在转基因小鼠的肺脏复制,而且转基因小鼠出现更严重的肺损伤。肺组织的损伤包括肺间质充血、出血,单核细胞、淋巴细胞浸润及血浆蛋白的渗出,肺泡上皮细胞增生、脱落,此外,在转基因小鼠的某些器官还发现了血管炎、变性和坏死等病理变化。在转基因小鼠的肺上皮细胞、血管内皮细胞和脑神经细胞检测到病毒抗原。结论转基因小鼠比野生型小鼠对SARS病毒更易感,而且表现出更接近SARS患者的病理变化。

Objective To establish a small animal model of severe acute respiratory syndrome （SARS） . Methods We developed a mouse model of human SARS coronavirus infection by introducing the human angiotensin converting enzyme 2 （hACE2） gene, serving as the cellular receptor of SARS coronavirus （SARS-CoV）, into the mouse genome. The hACE2 gene, driven by the mouse ACE2 promoter, was expressed in the lung, heart, kidney and intestines. The responses of wild-type and transgenic mice to SARS-CoV inoculation were observed. Results At 3 and 7 days after inoculation, SARS-CoV had replication more efficiently in the lungs of transgenic mice. In addition, transgenic mice showed more severe pulmonary lesions, including hyperaemia and haemorrhage in the interstitium, monocyte and lymphocyte infiltration, protein exudation, and alveolar epithelial cell proliferation and desquamation. Other pathological changes, including vasculitis, degeneration and necrosis were found in the extrapulmonary organs in transgenic mice. Viral antigen could be found in the lung and brain. Conclusions Transgenic mice are more susceptible to SARS-CoV infection than wild-type mice and the susceptibility is associated with severe pathological changes resembling human SARS infection.