INSERM U1259 MAVIVH, Tours University and Tours University Hospital, Tours, France.
UMR 1282 ISP, INRAe, Tours University, Nouzilly, France.
Hepatol Commun. 2023 Nov 8;7(11). doi: 10.1097/HC9.0000000000000274. eCollection 2023 Nov 1.
Hepatitis E virus (HEV) is a zoonotic virus transmitted by pig meat and responsible for chronic hepatitis E in immunocompromised patients. It has proved challenging to reproduce this disease in its natural reservoir. We therefore aimed to develop a pig model of chronic hepatitis E to improve the characterization of this disease.
Ten pigs were treated with a tacrolimus-based regimen and intravenously inoculated with HEV. Tacrolimus trough concentration, HEV viremia, viral diversity, innate immune responses, liver histology, clinical disease and biochemical markers were monitored for 11 weeks post-infection (p.i.).
HEV viremia persisted for 11 weeks p.i. HEV RNA was detected in the liver, small intestine, and colon at necropsy. Histological analysis revealed liver inflammation and fibrosis. Several mutations selected in the HEV genome were associated with compartmentalization in the feces and intestinal tissues, consistent with the hypothesis of extrahepatic replication in the digestive tract. Antiviral responses were characterized by a downregulation of IFN pathways in the liver, despite an upregulation of RIG-I and ISGs in the blood and liver.
We developed a pig model of chronic hepatitis E that reproduced the major hallmarks of this disease. This model revealed a compartmentalization of HEV genomes in the digestive tract and a downregulation of innate immune responses in the liver. These original features highlight the relevance of our model for studies of the pathogenesis of chronic hepatitis E and for validating future treatments.
戊型肝炎病毒（HEV）是一种通过猪肉传播的人畜共患病病毒，可导致免疫功能低下患者发生慢性戊型肝炎。在其自然宿主中重现这种疾病极具挑战性。因此，我们旨在开发一种慢性戊型肝炎猪模型，以改善对这种疾病的特征描述。
10 头猪接受了他克莫司方案治疗，并经静脉接种 HEV。在感染后 11 周（p.i.）监测他克莫司谷浓度、HEV 病毒血症、病毒多样性、先天免疫反应、肝组织学、临床疾病和生化标志物。
HEV 病毒血症持续了 11 周 p.i.。在尸检时，在肝脏、小肠和结肠中检测到 HEV RNA。组织学分析显示肝脏炎症和纤维化。在 HEV 基因组中选择的几个突变与粪便和肠道组织中的分隔有关，这与在消化道中存在肝外复制的假设一致。抗病毒反应的特征是肝脏中 IFN 途径下调，尽管血液和肝脏中 RIG-I 和 ISGs 上调。
我们开发了一种慢性戊型肝炎猪模型，重现了该疾病的主要特征。该模型揭示了 HEV 基因组在消化道中的分隔以及肝脏中先天免疫反应的下调。这些原始特征突出了我们模型在慢性戊型肝炎发病机制研究和验证未来治疗方法方面的相关性。
