State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ 070101, USA.
Antiviral Res. 2017 Oct;146:45-53. doi: 10.1016/j.antiviral.2017.08.012. Epub 2017 Aug 18.
Varicella pneumonia is one of the most serious, potentially life-threatening complications of primary varicella-zoster virus (VZV) infection in adults and immunocompromised individuals. However, studies on the lung pathogenesis of VZV infection as well as development and testing of antivirals have long been hindered by limited access to clinical samples and a lack of suitable animal models. In this study, we report for the first time the use of human lung xenografts in SCID mice for investigating VZV infection. Human fetal lung tissues grafted under the kidney capsule of SCID mice rapidly grew and developed mature structures closely resembling normal human lung. Following infection, VZV replicated and spread efficiently in human lung xenografts, where the virus targeted both alveolar epithelial and mesenchymal cells, and resulted in formation of large viral lesions. VZV particles were readily detected in the nuclei and cytoplasm of infected lung cells by electron microscopy. Additionally, VZV infection resulted in a robust pro-inflammatory cytokine response in human lung xenografts. In conclusion, infecting human lung xenografts in SCID mice provides a useful, biological relevant tool for future mechanistic studies on VZV lung pathogenesis, and may potentially facilitate the evaluation of new antiviral therapies for VZV lung infection.
水痘肺炎是成人和免疫功能低下者原发性水痘-带状疱疹病毒（VZV）感染最严重、潜在威胁生命的并发症之一。然而，长期以来，由于临床样本获取有限以及缺乏合适的动物模型，VZV 感染的肺部发病机制研究以及抗病毒药物的开发和测试一直受到阻碍。在这项研究中，我们首次报告了在 SCID 小鼠中使用人肺异种移植物来研究 VZV 感染。将人胎肺组织移植到 SCID 小鼠的肾脏包膜下，这些组织迅速生长并发育出与正常人类肺非常相似的成熟结构。感染后，VZV 在人肺异种移植物中高效复制和传播，病毒靶向肺泡上皮细胞和间充质细胞，并导致形成大的病毒病变。电镜下，很容易在感染的肺细胞的核和细胞质中检测到 VZV 颗粒。此外，VZV 感染导致人肺异种移植物中促炎细胞因子的强烈反应。总之，在 SCID 小鼠中感染人肺异种移植物为未来 VZV 肺部发病机制的机制研究提供了一种有用的、生物学相关的工具，并可能有助于评估 VZV 肺部感染的新抗病毒疗法。
