I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department for General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Germany.
J Hepatol. 2015 Aug;63(2):346-53. doi: 10.1016/j.jhep.2015.03.011. Epub 2015 Mar 17.
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.
Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence.
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-ß, hIFN-ß and hIFN-λ) 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.
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.
由于有限的丁型肝炎病毒（HDV）感染模型，阻碍了对 HDV 与受感染肝细胞相互作用的研究。本研究旨在通过人源化 uPA/SCID/beige（USB）小鼠，比较乙型肝炎病毒（HBV）单一感染与 HBV/HDV 共感染时，HDV 感染的人肝细胞的抗病毒状态。
通过 qRT-PCR、ELISA 和免疫荧光法，在人源化 USB 小鼠中检测病毒载量、人干扰素刺激基因（hISGs）和细胞因子。
HBV/HDV 接种后，所有小鼠均发生病毒血症，与未感染小鼠相比，hISGs（即 hISG15、hSTATs、hHLA-E）显著升高，而 HBV 单一感染导致 hISG 升高较弱。在慢性感染的情况下，HBV/HDV 感染小鼠的固有防御机制增强更为明显。此外，在 HBV/HDV 共感染动物中还检测到人类特异性细胞因子（hIP10、hTGF-β、hIFN-β和 hIFN-λ）的诱导，而在未感染和 HBV 单一感染小鼠中，这些细胞因子的水平较低或检测不到。此外，尽管在 HBV/HDV 感染的肝脏中确定 hSTAT 水平平均增加，但我们观察到在显示非常高 HDAg 水平的肝细胞中 hSTAT 积累较弱，这表明 HDAg 可能部分限制 hSTAT 信号传导。
建立 HDV 感染会明显增强嵌合小鼠中人类肝细胞的抗病毒状态。较高的预处理 ISG 和干扰素水平可能直接导致炎症和肝损伤，为 HDV 相关肝病更严重的病程提供了依据。这种抗病毒状态的诱导也可能有助于降低共感染肝细胞中经常发现的 HBV 活性水平。
