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.
Highlights
Toll-like receptors (TLRs), an important component of innate immunity, play crucial roles in sensing invaders and initiating innate immune responses, thereby limiting the spreading of infections and modulating adaptive immune responses[6]
We demonstrated, for the first time, that reactive oxygen species (ROS) levels were higher in sera and liver tissues from Hepatitis C virus (HCV)-infected tupaias than in that from uninfected tupaias
These data were consistent with previous findings of higher ROS levels in sera[28] and liver tissues[29, 30] of HCV-infected patients
Summary
Toll-like receptors (TLRs), an important component of innate immunity, play crucial roles in sensing invaders and initiating innate immune responses, thereby limiting the spreading of infections and modulating adaptive immune responses[6]. Persistent hepatic inflammation, cirrhosis, and HCC have been reported in patients following viral clearance[17] To solve these issues and develop an efficient vaccine against HCV, animal models are essential. Tupaias have been reported to be susceptible to several hepatotropic viruses that infect humans, including hepatitis B virus[23, 24], HCV25, 26, and hepatitis E virus[27], and can be developed as an immunocompetent animal infection model. In this study, we evaluated the susceptibility of tupaias to several viral strains of HCV and characterized the effects of HCV infection on ROS generation and its association with anti-DHCR24 antibody levels. We characterized humoral immune responses to viral proteins and established a qPCR assay to evaluate TLR, NTCP, and cytokine expression to characterize the innate immune response during HCV infection, which may provide significant insight into HCV pathogenesis
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