The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin BaoWei DengBaoying HuangHong GaoJiangning LiuLili RenQiang WeiPin YüYanfeng XuFeifei QiYajin QuFengdi LiQi LvWen‐Ching WangJing XueShuran GongMingya LiuGuanpeng WangShunyi WangZhiqi SongLinna ZhaoPeipei LiuLi ZhaoFei YeHuijuan WangWeimin ZhouNa ZhuZhen WeiHaisheng YuXiaojuan ZhangLi GuoLan ChenConghui WangYing WangXinming WangYan XiaoQiangming SunHongqi LiuFanli ZhuChunxia MaLingmei YanMengli YangJun HanWenbo XuWenjie TanXiaozhong PengQi JinGuizhen WuChuan Qin
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Abstract:
Abstract Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the Corona Virus Disease 2019 (COVID-19) cases in China has become a public health emergency of international concern (PHEIC). Based on angiotensin converting enzyme 2 (ACE2) as cell entry receptor of SARS-CoV, we used the hACE2 transgenic mice infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes and monocytes in alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, alveolar macrophages and alveolar epithelia. The phenomenon was not found in wild type mice with SARS-CoV-2 infection. The pathogenicity of SARS-CoV-2 in hACE2 mice was clarified and the Koch’s postulates were fulfilled as well, and the mouse model may facilitate the development of therapeutics and vaccines against SARS-CoV-2.Keywords:
Alveolar cells
Histopathology
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The use of the Cre-loxP recombination system allows the conditional inactivation of genes in mice. The availability of transgenic mice in which the Cre recombinase expression is highly cell type specific is a prerequisite to successfully use this system. We previously have characterized regulatory regions of the mouse flk-1 gene sufficient for endothelial cell-specific expression of the LacZ reporter gene in transgenic mice. These regions were fused to the Cre recombinase gene, and transgenic mouse lines were generated. In the resulting flk-1-Cre transgenic mice, specificity of Cre activity was determined by cross-breeding with the reporter mouse lines Rosa26R or CAG-CAT-LacZ. We examined double-transgenic mice at different stages of embryonic development (E9.5-E16.5) and organs of adult animals by LacZ staining. Strong endothelium-specific staining of most vascular beds was observed in embryos older than E11.5 in one or E13.5 in a second line. In addition, the neovasculature of experimental BFS-1 tumors expressed the transgene. These lines will be valuable for the conditional inactivation of floxed target genes in endothelial cells of the embryonic vascular system.
Cre recombinase
Gene targeting
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Transgenic mice are an important in vivo model for studying the function of single genes. Specific induction and tissue specific expression of the inserted genes are the great advantages of this system. However, there a risks in constructing transgenic mice and the interpretion of the experimental data. To prevent artefacts and to optimize the transgenic model, the experimental systems have to fulfill the following presets:
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AIM: To analyze the tissue morphologic phenotype and liver gene expression profile of hBIF transgenic mice. METHODS: Transgene expression was analyzed with RT-PCR and Western blotting. For one of the transgenic mouse lines, tissue expression pattern of the transgene was also examined with immunochemical methods. Pathological analysis was used to examine the tissue morphologic phenotype of established transgenic mice. The liver gene expression profile of transgenic mice was analyzed with microchip, and some of bhe differentially expressed genes were verified with RT-PCR. RESULTS: The expressions of hBIF were shown in livers from 6 of 7 transgenic mouse lines. The overexpression of hB1F transgene did not cause pathological changes. Expressions of three genes were up-regulated, while down-regulation was observed for 25 genes. CONCLUSION: The overexpression of hBIF transgene may cause changes of gene expression profiles in the liver of transgenic mice.
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What are transgenic mice and what do we learn from them? In this review, we focus on the generation of "classical" transgenic and "knock-out" mice. The establishment of transgenic and gene-targeted mice provides an unique tool to study the function(s) of a given gene in the context of a whole organism. Based on selected examples, we demonstrate the potential of this transgenic technology to understand the interactions between cells, organs and organ systems in genetically engineered mice.
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AIM:To analyze the tissue morphologic phenotype and liver gene expression profile of hB1F transgenic mice. METHODS:Transgene expression was analyzed with RT-PCR and Western blotting.For one of the transgenic mouse lines, tissue expression pattern of the transgene was also examined with immunochemical methods.Pathological analysis was used to examine the tissue morphologic phenotype of established transgenic mice.The liver gene expression profile of transgenic mice was analyzed with microchip, and some of the differentially expressed genes were verified with RT-PCR. RESULTS:The expressions of hB1F were shown in livers from 6 of 7 transgenic mouse lines.The overexpression of hB1F transgene did not cause pathological changes.Expressions of three genes were up-regulated, while down-regulation was observed for 25 genes. CONCLUSION:The overexpression of hB1F transgene may cause changes of gene expression profiles in the liver of transgenic mice.
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Transgenic mice have had a tremendous impact on biomedical research. Most researchers are familiar with transgenic mice that carry Cre recombinase (Cre) and how they are used to create conditional knockouts. However, some researchers are less familiar with many of the other types of transgenic mice and their applications. For example, transgenic mice can be used to study biochemical and molecular pathways in primary cultures and cell suspensions derived from transgenic mice, cell-cell interactions using multiple fluorescent proteins in the same mouse, and the cell cycle in real time and in the whole animal, and they can be used to perform deep tissue imaging in the whole animal, follow cell lineage during development and disease, and isolate large quantities of a pure cell type directly from organs. These novel transgenic mice and their applications provide the means for studying of molecular and biochemical events in the whole animal that was previously limited to cell cultures. In conclusion, transgenic mice are not just for generating knockouts.
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Cre recombinase
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