Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation
Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation
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DOI：
10.1016/j.jhep.2016.01.011
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发表时间：
2016-05-01
影响因子：
25.7
通讯作者：
Luetgehetmann, Marc
中科院分区：
文献类型：
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作者：
Allweiss, Lena;Gass, Sofia;Luetgehetmann, Marc
背景和目标：戊型肝炎病毒（HEV）是急性肝炎以及免疫功能低下个体慢性感染的主要原因;然而，体内感染模型有限。本研究的目的是建立一个小的动物模型，以提高我们的理解HEV复制机制，并允许开发有效的therapeutics.Methods：UPA/SCID/beige小鼠重新填充与原代人肝细胞用于感染实验与HEV基因型（GT）1和3。通过真实的时间PCR、免疫组化和RNA原位杂交技术，在血清学和肝内水平测定病毒学参数。结果：静脉注射粪便来源的病毒颗粒后，与HEV感染的动物共饲养，可建立HEV感染，但不通过接种血清来源的HEV。GT 1感染导致感染小鼠血清、肝脏、胆汁和粪便中病毒血症迅速上升，并在超过25周的时间内保持高稳定滴度。相比之下，与GT 1相比，GT 3感染小鼠的病毒血症发展更慢，并且在所有分析的组织中显示出更低的滴度。HEV感染的人肝细胞可以可视化使用HEV ORF 2和ORF 3特异性抗体和HEV RNA原位杂交探针。最后，6周的利巴韦林给药导致了一个强大的减少病毒复制在血清和肝GT 1 infected mice.Conclusion：我们建立了一个有效的模型，戊型肝炎病毒感染的抗病毒药物的效力，并探讨在体内的戊型肝炎病毒复制和与人肝细胞相互作用的机制。(C)2016年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Hepatitis E virus (HEV) is a major cause of acute hepatitis as well as chronic infection in immunocompromised individuals; however, in vivo infection models are limited. The aim of this study was to establish a small animal model to improve our understanding of HEV replication mechanisms and permit the development of effective therapeutics.Methods: UPA/SCID/beige mice repopulated with primary human hepatocytes were used for infection experiments with HEV genotype (GT) 1 and 3. Virological parameters were determined at the serological and intrahepatic level by real time PCR, immunohistochemistry and RNA in situ hybridization.Results: Establishment of HEV infection was achieved after intravenous injection of stool-derived virions and following co-housing with HEV-infected animals but not via inoculation of serum-derived HEV. GT 1 infection resulted in a rapid rise of viremia and high stable titres in serum, liver, bile and faeces of infected mice for more than 25 weeks. In contrast, viremia in GT 3 infected mice developed more slowly and displayed lower titres in all analysed tissues as compared to GT 1. HEV-infected human hepatocytes could be visualized using HEV ORF2 and ORF3 specific antibodies and HEV RNA in situ hybridization probes. Finally, six week administration of ribavirin led to a strong reduction of viral replication in the serum and liver of GT 1 infected mice.Conclusion: We established an efficient model of HEV infection to test the efficacy of antiviral agents and to exploit mechanisms of HEV replication and interaction with human hepatocytes in vivo. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.