Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
J Virol. 2012 Jun;86(11):6286-302. doi: 10.1128/JVI.00205-12. Epub 2012 Mar 28.
We have recently reported that a group of human adenoviruses (HAdVs) uses desmoglein 2 (DSG2) as a receptor for infection. Among these are the widely distributed serotypes HAdV-B3 and HAdV-B7, as well as a newly emerged strain derived from HAdV-B14. These serotypes do not infect rodent cells and could not up until now be studied in small-animal models. We therefore generated transgenic mice containing the human DSG2 locus. These mice expressed human DSG2 (hDSG2) at a level and in a pattern similar to those found for humans and nonhuman primates. As an initial application of hDSG2-transgenic mice, we used a green fluorescent protein (GFP)-expressing HAdV-B3 vector (Ad3-GFP) and studied GFP transgene expression by quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemistry subsequent to intranasal and intravenous virus application. After intranasal application, we found efficient transduction of bronchial and alveolar epithelial cells in hDSG2-transgenic mice. Intravenous Ad3-GFP injection into hDSG2-transgenic mice resulted in hDSG2-dependent transduction of epithelial cells in the intestinal and colon mucosa. Our findings give an explanation for clinical symptoms associated with infection by DSG2-interacting HAdVs and provide a rationale for using Ad3-derived vectors in gene therapy.
我们最近报道了一组人腺病毒（HAdV）利用桥粒芯糖蛋白 2（DSG2）作为感染的受体。其中包括广泛分布的血清型 HAdV-B3 和 HAdV-B7，以及一种源自 HAdV-B14 的新出现的菌株。这些血清型不感染啮齿动物细胞，到目前为止，它们不能在小动物模型中进行研究。因此，我们生成了含有人类 DSG2 基因座的转基因小鼠。这些小鼠表达与人和非人类灵长类动物相似水平和模式的人 DSG2（hDSG2）。作为 hDSG2 转基因小鼠的初步应用，我们使用了一种表达绿色荧光蛋白（GFP）的 HAdV-B3 载体（Ad3-GFP），并通过定量逆转录 PCR（qRT-PCR）和免疫组织化学研究了鼻内和静脉病毒应用后 GFP 转基因的表达。鼻内应用后，我们发现 hDSG2 转基因小鼠的支气管和肺泡上皮细胞有有效的转导。静脉内注射 Ad3-GFP 到 hDSG2 转基因小鼠中，导致 hDSG2 依赖性肠和结肠黏膜上皮细胞的转导。我们的研究结果解释了与 DSG2 相互作用的 HAdV 感染相关的临床症状，并为使用 Ad3 衍生载体进行基因治疗提供了依据。
