Hepatic inflammation mediated by hepatitis C virus core protein is ameliorated by blocking complement activation

Area of Science:

• Hepatology
• Virology
• Immunology

Background:

• The precise mechanisms driving inflammation and fibrosis in chronic hepatitis C virus (HCV) infection are not fully understood.
• Existing transgenic mouse models overexpressing HCV core protein from gestation show only steatosis, differing from human post-natal infection.
• This highlights the need for models that mimic adult-onset HCV infection for accurate pathogenesis studies.

Purpose of the Study:

• To develop a more accurate mouse model of adult liver disease by studying conditional HCV core protein expression.
• To investigate the role of the complement pathway in HCV-induced liver pathology.

Main Methods:

• Conditional expression of HCV core protein in adult mice using a tetracycline-regulated system.
• Immunohistological evaluation of liver biopsy samples from transgenic mice.
• Microarray analysis to identify molecular pathways involved in HCV-induced steatohepatitis.
• In vivo administration of CD55 (decay accelerating factor for complement) to inhibit complement activation.

Main Results:

• Mice with intermediate HCV core protein expression developed hepatic steatosis, inflammation, and fibrosis.
• Microarray analysis revealed activation of complement (C3 up-regulation) and coagulation (fibrinogen B up-regulation) pathways in inflamed livers.
• Administration of CD55 significantly reduced hepatic inflammation.

Conclusions:

• Conditional expression of intermediate HCV core protein in adult mice recapitulates key features of chronic hepatitis C, including inflammation, steatosis, and fibrosis.
• The complement regulator CD55 effectively mitigated HCV core-induced liver inflammation, implicating the complement pathway in pathogenesis.
• This novel conditional mouse model is valuable for studying the pathogenesis of liver inflammation in chronic hepatitis C.