Novel animal models to study organ-specific SARS-CoV-2-induced pathology

越来越多的证据表明，SARS-CoV-2感染可诱导多个器官的组织病理学， 除了肺之外，还包括肠、心脏、肝脏、肾脏和脑。此外，SARS- CoV-2感染可加重许多慢性炎症性疾病。然而，小鼠模型， 研究SARS-CoV-2在特定器官中诱导的病理学目前缺乏。此外，治疗 使用市售K18-hACE 2转基因小鼠模型的策略由于异位妊娠而受到限制。 hACE 2在脑中的表达驱动高致死性。为了克服这些问题，我们培育了 条件性组织特异性hACE 2表达。这项提案的目的是描述这些小说的特点， 小鼠模型，并明确SARS-CoV-2对肺免疫病理学和肠 疾病我们的中心假设是，在Rosa 26基因座中有条件表达hACE 2的小鼠， 代表了研究组织特异性SARS-CoV-2诱导的病理学的强大平台。在目标1中，我们将测试 hACE 2在II型肺泡上皮细胞和俱乐部细胞中表达是必需的假设， 足以用于SARS-CoV-2诱导的肺免疫病理学。我们将分析SARS-CoV-2感染 Ⅱ型肺泡上皮特异性表达hACE 2小鼠肺动力学及免疫病理学研究 细胞和俱乐部细胞，使用我们最近开发的双报告基因表达mCherry-Nluc重组体 （r）SARS-CoV-2。在目标2中，我们将检验SARS-CoV-2感染加重肠道疾病的假设， 使用在肠上皮细胞中特异性表达hACE 2的小鼠观察炎症。这项建议是 创新和重要，因为它将产生和表征新的小动物模型来研究SARS- CoV-2介导的器官特异性疾病，并为SARS-CoV-2介导的肺机制提供见解 和肠道病理学这些小鼠模型将为研究和监测SARS-CoV-2提供一个强大的平台 感染所需的细胞类型和SARS-CoV-2感染的长期并发症，并进行 治疗干预。

Accumulating evidence suggest that SARS-CoV-2 infection induces tissue pathology in multiple organs in addition to the lung, including, among others, intestine, heart, liver, kidney, and brain. Furthermore, SARS- CoV-2 infection can exacerbate many chronic inflammatory diseases. However, mouse models that allow to study SARS-CoV-2-induced pathology in specific organs are currently lacking. Additionally, therapeutic strategies using the commercially available K18-hACE2 transgenic mouse model are limited due to ectopic hACE2 expression in the brain driving high lethality. To overcome these problems, we have generated mice with conditional tissue-specific hACE2 expression. The goal of this proposal is to characterize these novel mouse models and define the impact of SARS-CoV-2 specifically on lung immunopathology and intestinal disease. Our central hypothesis is that mice with conditional expression of hACE2 in Rosa26 locus represent a robust platform to study tissue-specific SARS-CoV-2-induced pathology. In Aim 1, we will test the hypothesis that hACE2 expression in type II alveolar epithelial cells and club cells is necessary and sufficient for SARS-CoV-2-induced lung immunopathology. We will analyze SARS-CoV-2 infection dynamics and lung immunopathology in mice with specific expression of hACE2 in type II alveolar epithelial cells and club cells, using our recently developed dual reporter- expressing mCherry-Nluc recombinant (r)SARS-CoV-2. In Aim 2, we will test the hypothesis that SARS-CoV-2 infection exacerbates intestinal inflammation using mice with specific expression of hACE2 in intestinal epithelial cells. This proposal is innovative and significant, as it will generate and characterize novel small animal models to study SARS- CoV-2 mediated organ-specific disease and provide insights into mechanisms of SARS-CoV-2-mediated lung and gut pathology. These mouse models will provide a robust platform to study and monitor SARS-CoV-2 infection in desired cell types and long-term complications of SARS-CoV-2 infection, and to perform therapeutic interventions.