Conjugated bilirubin reduces hepatitis E virus infectivity by modulating immunometabolic processes

Area of Science:

• Hepatology
• Immunology
• Virology

Background:

• Hepatitis E virus (HEV) is a major cause of viral hepatitis globally, yet lacks approved treatments or vaccines.
• The role of metabolic factors, like conjugated bilirubin (cBR), in HEV infection is not well understood.
• Previous research suggested cBR has immunomodulatory and potential antiviral effects in hepatitis A virus infection.

Purpose of the Study:

• To investigate the impact of conjugated bilirubin (cBR) on hepatitis E virus (HEV) infectivity.
• To elucidate the mechanisms by which cBR influences HEV infection, focusing on immune and metabolic interactions.
• To assess cBR's potential as a therapeutic agent for HEV.

Main Methods:

• Ex vivo analysis of HEV-infected patients.
• In vitro antigenic restimulation of peripheral blood mononuclear cells (PBMCs) with varying cBR concentrations.
• In vitro infection of HEV-permissive cell lines.

Main Results:

• cBR at 2 mg/dL reduced HEV viral titers and increased IFN-γ release in acute infections.
• cBR (2 mg/dL) enhanced interactions between TNF-α and metabolic proteins (Akt, ERK) in PBMCs.
• cBR (≥0.3 mg/dL) boosted IFN-γ production by CD8+ T cells and decreased viral titers in acute and chronic HEV models.

Conclusions:

• Conjugated bilirubin (cBR) significantly modulates immune and metabolic components during HEV infection.
• cBR demonstrates antiviral effects against HEV, reducing viral load and enhancing immune responses.
• These findings highlight cBR's potential as a therapeutic strategy for hepatitis E.