Department of Pathological and Preventive Veterinary Science, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.
Laboratory of Animal Hygiene, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
Sci Rep. 2017 Aug 29;7(1):9848. doi: 10.1038/s41598-017-10329-7.
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. To address the molecular basis of HCV pathogenesis using tupaias (Tupaia belangeri), we characterized host responses upon HCV infection. Adult tupaias were infected with HCV genotypes 1a, 1b, 2a, or 4a. Viral RNA, alanine aminotransferase, anti-HCV core and anti-nonstructural protein NS3 antibody titres, reactive oxygen species (ROS), and anti-3β-hydroxysterol-Δ24reductase (DHCR24) antibody levels were measured at 2-week intervals from 0 to 41 weeks postinfection. All HCV genotypes established infections and showed intermittent HCV propagation. Moreover, all tupaias produced anti-core and anti-NS3 antibodies. ROS levels in sera and livers were significantly increased, resulting in induction of DHCR24 antibody production. Similarly, lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis were observed in livers from HCV-infected tupaias. Intrahepatic levels of Toll-like receptors 3, 7, and 8 were significantly increased in all HCV-infected tupaias. However, interferon-β was only significantly upregulated in HCV1a- and HCV2a-infected tupaias, accompanied by downregulation of sodium taurocholate cotransporting polypeptide. Thus, our findings showed that humoral and innate immune responses to HCV infection, ROS induction, and subsequent increases in DHCR24 auto-antibody production occurred in our tupaia model, providing novel insights into understanding HCV pathogenesis.
丙型肝炎病毒（HCV）是慢性肝病、肝硬化和肝细胞癌的主要病因。为了利用食蟹猴（Tupaia belangeri）来研究 HCV 发病机制的分子基础，我们对 HCV 感染后的宿主反应进行了特征描述。成年食蟹猴感染 HCV 基因型 1a、1b、2a 或 4a。在感染后 0 至 41 周的 2 周间隔内，测量了病毒 RNA、丙氨酸转氨酶、抗 HCV 核心和抗非结构蛋白 NS3 抗体滴度、活性氧（ROS）和抗 3β-羟甾醇-Δ24 还原酶（DHCR24）抗体水平。所有 HCV 基因型均建立了感染，并显示间歇性 HCV 增殖。此外，所有食蟹猴均产生了抗核心和抗 NS3 抗体。血清和肝脏中的 ROS 水平显著增加，导致 DHCR24 抗体产生的诱导。同样，在 HCV 感染的食蟹猴肝脏中观察到淋巴细胞浸润、肝索紊乱和纤维化的启动。所有 HCV 感染的食蟹猴肝内 Toll 样受体 3、7 和 8 的水平均显著升高。然而，干扰素-β仅在 HCV1a 和 HCV2a 感染的食蟹猴中显著上调，同时伴随着钠牛磺胆酸盐共转运蛋白的下调。因此，我们的研究结果表明，HCV 感染后的体液和先天免疫反应、ROS 诱导以及随后 DHCR24 自身抗体的产生增加，在我们的食蟹猴模型中发生，为理解 HCV 发病机制提供了新的见解。
