Hepatitis C virus proteins inhibit C3 complement production

Area of Science:

• Immunology
• Virology
• Hepatology

Background:

• The third component of human complement (C3) is crucial for innate immune responses, activating both classical and alternative complement pathways.
• Chronic hepatitis C virus (HCV) infection can lead to immune dysregulation, but its specific impact on complement pathways remains incompletely understood.

Purpose of the Study:

• To investigate the effect of chronic hepatitis C virus (HCV) infection on complement component 3 (C3) levels and expression.
• To elucidate the mechanisms by which HCV proteins influence C3 production and innate immune function.

Main Methods:

• Quantification of C3 levels in sera from HCV patients and healthy individuals.
• Measurement of C3 mRNA expression in liver biopsy specimens and cultured hepatocytes.
• Analysis of C3 promoter activity and transcription factor regulation by HCV core and NS5A proteins in vitro.

Main Results:

• HCV-infected patients exhibited significantly lower serum C3 levels and reduced C3 mRNA expression in liver tissues compared to healthy controls.
• HCV infection in hepatocytes in vitro led to decreased C3 mRNA levels.
• HCV core protein weakly repressed C3 promoter activity via downregulation of FXR, while NS5A protein strongly inhibited C3 promoter activity, irrespective of IL-1β induction.
• Expression of C/EBP-β, a key transcription factor for C3, was reduced in HCV-infected liver tissues and hepatocytes.

Conclusions:

• Chronic HCV infection impairs innate immune function by significantly reducing complement component 3 (C3) levels.
• The HCV NS5A protein plays a critical role in this immune impairment by strongly downregulating C3 production through inhibition of transcription factors like C/EBP-β.