Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection
Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection
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DOI：
10.1016/j.jhep.2015.03.011
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发表时间：
2015-08-01
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：
Giersch, Katja;Allweiss, Lena;Luetgehetmann, Marc
背景和目标：丁型肝炎病毒（HDV）感染模型的有限性阻碍了HDV和感染肝细胞之间相互作用的研究。目的是研究HDV感染的人肝细胞在与B肝炎病毒（HBV）共感染的情况下的抗病毒状态，与使用人肝嵌合体小鼠的HBV单一感染相比。方法：通过qRT-PCR、ELISA和免疫荧光法测定人源化uPA/SCID/beige（USB）小鼠中的病毒载量、人干扰素刺激基因（hISGs）和细胞因子。在HBV/HDV接种后，所有小鼠均发生病毒血症，与未感染的小鼠相比，其伴随hISG（即hISG 15、hSTAT、hHLA-E）的显著诱导，而HBV单一感染导致较弱的hISG升高。在慢性感染的情况下，先天防御机制的增强在HBV/HDV感染的小鼠中显著更突出。在HBV/HDV共感染的动物中也检测到人特异性细胞因子（hIP 10、hTGF-β、hIFN-β和hIFN-λ）的诱导，而在未感染和HBV单感染的小鼠中水平保持较低或低于检测。此外，尽管在HBV/HDV感染的肝脏中确定的hSTAT水平的平均增加，我们观察到一个较弱的hSTAT积累在肝细胞的细胞核显示非常高的HDAg水平，这表明HDAg可能在一定程度上限制hSTAT signaling.Conclusions：HDV感染的建立引起了明显的增强嵌合小鼠中的人肝细胞的抗病毒状态。治疗前ISG和干扰素水平升高可能直接导致炎症和肝损伤，为更严重的HDV相关肝病病程提供了理论基础。这种抗病毒状态的诱导也可能导致在共同感染的肝细胞中经常发现的较低水平的HBV活性。(C)2015年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice.Methods: Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence.Results: Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-beta, hIFN-beta and hIFN-lambda) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling.Conclusions: Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.