Oxidative Stress and Immune Responses During Hepatitis C Virus Infection in Tupaia belangeri

Abstract

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.

Pathogenesis and Immune Response Caused by Vector-Borne and Other Viral Infections in a Tupaia Model

“…In the same study, we also characterized TLR mRNA expression, and similar to studies in humans, we found increased intrahepatic levels of TLRs 3, 7, and 8 [19]. Remarkably, HCV infection in Tupaia triggered ROS generation in sera and liver tissues and subsequently induced anti-3β-hydroxysterol-∆24-reductase (DHCR24) antibody production [19], similar to observations in human infections [51][52][53][54][55]. A previous study demonstrated anti-DHCR24 auto-antibodies as a biomarker for Hepatitis C progression [56] and the findings of HCV chronic infection in Tupaia also supported the possibility of using anti-DHCR24 antibodies as a valuable marker to monitor HCV infection in vivo.…”

“…Several studies have demonstrated the susceptibility of Tupaia to infections with different HCV strains, where the disease course of chronic HCV infection was comparable to that observed in humans. However, sustained/intermittent propagation of HCV with medium/low viral loads were observed in Tupaia, which might be associated with a more restricted replication of HCV in Tupaia compared to humans [17][18][19]. In chronic HCV infection, histopathological findings, including lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis in the liver of HCV-infected Tupaia were observed; these findings were similar to those observed in human patients [19].…”

“…In addition, Amako et al showed that infection of naïve animals with viral RNA-positive Tupaia serum could establish re-infection, which was indicated by the development of acute hepatitis and viremia, suggesting that HCV infection in Tupaia could reproduce the pathogenesis typically associated with acute and chronic hepatitis [18]. In a recent study, we demonstrated the generation of anti-core and anti-NS3 antibodies in HCV infection in a Tupaia model, which suggests the potential of using Tupaia in vaccine experiments [19]. In the same study, we also characterized TLR mRNA expression, and similar to studies in humans, we found increased intrahepatic levels of TLRs 3, 7, and 8 [19].…”

“…In a recent study, we demonstrated the generation of anti-core and anti-NS3 antibodies in HCV infection in a Tupaia model, which suggests the potential of using Tupaia in vaccine experiments [19]. In the same study, we also characterized TLR mRNA expression, and similar to studies in humans, we found increased intrahepatic levels of TLRs 3, 7, and 8 [19]. Remarkably, HCV infection in Tupaia triggered ROS generation in sera and liver tissues and subsequently induced anti-3β-hydroxysterol-∆24-reductase (DHCR24) antibody production [19], similar to observations in human infections [51][52][53][54][55].…”

“…However, sustained/intermittent propagation of HCV with medium/low viral loads were observed in Tupaia, which might be associated with a more restricted replication of HCV in Tupaia compared to humans [17][18][19]. In chronic HCV infection, histopathological findings, including lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis in the liver of HCV-infected Tupaia were observed; these findings were similar to those observed in human patients [19]. Previous studies have reported the development of liver cirrhosis and hepatocellular carcinoma in Tupaia during HCV chronic infection [18].…”