Usai Carla, Maestro Sheila, Camps Gracian, Olague Cristina, Suárez-Amaran Lester, Vales Africa, Aragon Tomas, Hommel Mirja, Aldabe Rafael, Gonzalez-Aseguinolaza Gloria
Gene Therapy and Regulation of Gene Expression Program, CIMA, University of Navarra, Instituto de Investigacion Sanitaria de Navarra, IdisNA, Pamplona, Spain.
JHEP Rep. 2020 Mar 10;2(3):100098. doi: 10.1016/j.jhepr.2020.100098. eCollection 2020 Jun.
BACKGROUND & AIMS: HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected.
HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte death were evaluated and the immune infiltrate was characterized. Liver transcriptomic analysis was performed. Mice deficient for different cellular and molecular components of the immune system, as well as depletion and inhibition studies, were employed to elucidate the causes of HDV-mediated liver damage.
AAV-mediated HBV/HDV coinfection caused hepatocyte necrosis and apoptosis. Activated T lymphocytes, natural killer cells, and proinflammatory macrophages accounted for the majority of the inflammatory infiltrate. However, depletion studies and the use of different knockout mice indicated that neither T cells, natural killer cells nor macrophages were necessary for HDV-induced liver damage. Transcriptomic analysis revealed a strong activation of type I and II interferon (IFN) and tumor necrosis factor (TNF)-α pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-α antagonist resulted in a significant reduction of HDV-associated liver injury. Furthermore, hepatic expression of HDAg resulted in the induction of severe liver damage, which was T cell- and TNF-α-independent.
Both host (TNF-α) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-α may offer an attractive strategy to aid control of HDV-induced acute liver damage.
Chronic hepatitis delta constitutes the most severe form of viral hepatitis. There is limited data on the mechanism involved in hepatitis delta virus (HDV)-induced liver pathology. Our data indicate that a cytokine (TNF-α) and HDV antigens play a relevant role in HDV-induced liver damage.
丁型肝炎病毒（HDV）感染可引发最严重的人类病毒性肝炎。然而，该病病情严重的具体原因尚不清楚。最近，我们建立了一种HDV复制小鼠模型，首次在该模型中检测到了肝脏损伤。
使用腺相关病毒（AAV）将具有HDV和HBV复制能力的基因组以及HDV抗原递送至小鼠肝细胞。评估转氨酶升高情况、肝脏组织病理学及肝细胞死亡情况，并对免疫浸润进行特征分析。进行肝脏转录组分析。利用免疫系统不同细胞和分子成分缺陷的小鼠，以及进行细胞耗竭和抑制研究，以阐明HDV介导的肝脏损伤的原因。
AAV介导的HBV/HDV共感染导致肝细胞坏死和凋亡。活化的T淋巴细胞、自然杀伤细胞和促炎性巨噬细胞占炎性浸润的大部分。然而，细胞耗竭研究以及使用不同基因敲除小鼠表明，T细胞、自然杀伤细胞和巨噬细胞对于HDV诱导的肝脏损伤均非必需。转录组分析显示，HBV/HDV共感染小鼠中I型和II型干扰素（IFN）以及肿瘤坏死因子（TNF）-α通路强烈激活。虽然缺乏IFN信号传导没有影响，但使用TNF-α拮抗剂可使HDV相关的肝损伤显著减轻。此外，HDAg的肝脏表达导致严重肝损伤的诱导，这与T细胞和TNF-α无关。
宿主（TNF-α）和病毒（HDV抗原）因素在HDV诱导的肝脏损伤中均发挥相关作用。重要的是，TNF-α的药理学抑制可能为辅助控制HDV诱导的急性肝损伤提供一种有吸引力的策略。
慢性丁型肝炎是最严重的病毒性肝炎形式。关于丁型肝炎病毒（HDV）诱导肝脏病理的机制的数据有限。我们的数据表明一种细胞因子（TNF-α）和HDV抗原在HDV诱导的肝脏损伤中发挥相关作用。
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