Transcriptome analysis reveals distinct immune response profiles in HBeAg+ and HBeAg− HBV infection and in HBV/HDV co-infection

Abstract

Abstract In chronic hepatitis B virus (HBV) infection, HBeAg positivity is associated with an increase in liver inflammation and progression to liver cirrhosis and cancer. Super-infection with hepatitis D virus (HDV) results in more severe liver disease. The causative factors are unknown. To understand the unique immunopathogenesis of HBeAg+ chronic HBV infection and chronic HBV/HDV co-infection, we performed a comparative transcriptome analysis using peripheral blood mononuclear cells of 12 HBV infected patients (6 HBeAg+ vs. 6 HBeAg−), 10 HBV/HDV co-infected patients, and 12 uninfected controls using NanoString human immunology V2 panel. About half of the differentially expressed genes in HBeAg+ versus HBeAg− HBV patients were interferon-stimulated genes (ISGs), and 83% of these ISGs (5/6) were upregulated. Ingenuity Pathway Analysis identified IFNA2 and IFNL1 as the most activated upstream regulators associated with HBeAg+ status. In contrast, only 7 out of 31 differentially expressed genes in chronic HBV/HDV co-infection compared to chronic HBV infection were ISGs, which were either upregulated or downregulated, indicating that IFN-signature is marginally involved in the pathogenesis of chronic HBV/HDV co-infection. Instead, Ingenuity Pathway Analysis identified CD40LG and IL18 as the most activated upstream regulators, and IRF activation by cytosolic pattern receptors and B cell receptor signaling as the top canonical pathways associated with chronic HBV/HDV co-infection. Our data suggest that IFN signaling may play a role in the enhanced liver disease found in chronic HBeAg+ HBV infection, and that CD40LG and IL18 signaling may contribute to unique immunopathogenesis of chronic HDV/HBV co-infection.