State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Guangdong Laboratory of Computational Biomedicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
J Virol. 2020 Aug 17;94(17). doi: 10.1128/JVI.00747-20.
Human adenovirus type 55 (HAdV55) represents an emerging respiratory pathogen and causes severe pneumonia with high fatality in humans. The cellular receptors, which are essential for understanding the infection and pathogenesis of HAdV55, remain unclear. In this study, we found that HAdV55 binding and infection were sharply reduced by disrupting the interaction of viral fiber protein with human desmoglein-2 (hDSG2) but only slightly reduced by disrupting the interaction of viral fiber protein with human CD46 (hCD46). Loss-of-function studies using soluble receptors, blocking antibodies, RNA interference, and gene knockout demonstrated that hDSG2 predominantly mediated HAdV55 infection. Nonpermissive rodent cells became susceptible to HAdV55 infection when hDSG2 or hCD46 was expressed, but hDSG2 mediated more efficient HAd55 infection than hCD46. We generated two transgenic mouse lines that constitutively express either hDSG2 or hCD46. Although nontransgenic mice were resistant to HAdV55 infection, infection with HAdV55 was significantly increased in hDSG2 mice but was much less increased in hCD46 mice. Our findings demonstrate that both hDSG2 and hCD46 are able to mediate HAdV55 infection but hDSG2 plays the major roles. The hDSG2 transgenic mouse can be used as a rodent model for evaluation of HAdV55 vaccine and therapeutics. Human adenovirus type 55 (HAdV55) has recently emerged as a highly virulent respiratory pathogen and has been linked to severe and even fatal pneumonia in immunocompetent adults. However, the cellular receptors mediating the entry of HAdV55 into host cells remain unclear, which hinders the establishment of HAdV55-infected animal models and the development of antiviral approaches. In this study, we demonstrated that human desmoglein-2 (hDSG2) plays the major roles during HAdV55 infection. Human CD46 (hCD46) could also mediate the infection of HAdV55, but the efficiency was much lower than for hDSG2. We generated two transgenic mouse lines that express either hDSG2 or hCD46, both of which enabled HAd55 infection in otherwise nontransgenic mice. hDSG2 transgenic mice enabled more efficient HAdV55 infection than hCD46 transgenic mice. Our study adds to our understanding of HAdV55 infection and provides an animal model for evaluating HAdV55 vaccines and therapeutics.
人腺病毒 55 型（HAdV55）是一种新兴的呼吸道病原体，可导致人类发生严重肺炎并导致高死亡率。细胞受体对于理解 HAdV55 的感染和发病机制至关重要，但目前仍不清楚。在这项研究中，我们发现破坏病毒纤维蛋白与人类桥粒芯糖蛋白 2（hDSG2）的相互作用可明显降低 HAdV55 的结合和感染，但破坏病毒纤维蛋白与人类 CD46（hCD46）的相互作用仅略微降低 HAdV55 的结合和感染。使用可溶性受体、阻断抗体、RNA 干扰和基因敲除进行的功能丧失研究表明，hDSG2 主要介导 HAdV55 感染。当表达 hDSG2 或 hCD46 时，非允许性啮齿动物细胞对 HAdV55 感染变得敏感，但 hDSG2 介导的 HAd55 感染比 hCD46 更有效。我们生成了两种稳定表达 hDSG2 或 hCD46 的转基因小鼠系。尽管非转基因小鼠对 HAdV55 感染具有抗性，但 HAdV55 在 hDSG2 小鼠中的感染显著增加，而在 hCD46 小鼠中的感染增加则要少得多。我们的研究结果表明，hDSG2 和 hCD46 均能够介导 HAdV55 感染，但 hDSG2 起主要作用。hDSG2 转基因小鼠可用作评估 HAdV55 疫苗和治疗剂的啮齿动物模型。人腺病毒 55 型（HAdV55）最近成为一种高毒力的呼吸道病原体，与免疫功能正常的成年人发生严重甚至致命性肺炎有关。然而，介导 HAdV55 进入宿主细胞的细胞受体仍不清楚，这阻碍了 HAdV55 感染动物模型的建立和抗病毒方法的发展。在这项研究中，我们证明了人桥粒芯糖蛋白 2（hDSG2）在 HAdV55 感染过程中起主要作用。人 CD46（hCD46）也可以介导 HAdV55 的感染，但效率远低于 hDSG2。我们生成了两种表达 hDSG2 或 hCD46 的转基因小鼠系，这两种系均使原本非转基因的小鼠能够感染 HAd55。hDSG2 转基因小鼠比 hCD46 转基因小鼠更能有效地感染 HAdV55。我们的研究增加了对 HAdV55 感染的认识，并提供了一种评估 HAdV55 疫苗和治疗剂的动物模型。
