Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen

S. Jegaskanda, S. H. Ahn, N. Skinner, A. J. Thompson, T. Ngyuen, J. Holmes, R. de Rose, M. Navis, W. R. Winnall, M. Kramski, G. Bernardi, J. Bayliss, D. Colledge, V. Sozzi, K. Visvanathan, S. A. Locarnini, S. J. Kent, P. A. Revill

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Abstract

The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHB) are poorly defined. Innate immune responses play an important role in reducing HBV replication and pathogenesis. HBV has developed numerous mechanisms to escape these responses, including the production of the secreted hepatitis B e antigen (HBeAg), which has been shown to regulate antiviral toll-like receptor (TLR) and interleukin-1 (IL-1) signaling. IL-18 is a related cytokine that inhibits HBV replication in hepatoma cell lines and in the liver through the induction of gamma interferon (IFN-γ) by NK cells and T cells. We hypothesized that HBV or HBV proteins inhibit IFN-γ expression by NK cells as an accessory immunomodulatory function. We show that HBeAg protein inhibits the NF-κB pathway and thereby downregulates NK cell IFN-γ expression. Additionally, IFN-γ expression was significantly inhibited by exposure to serum from individuals with HBeAg-positive but not HBeAg-negative chronic HBV infection. Further, we show that the HBeAg protein suppresses IL-18-mediated NF-κB signaling in NK and hepatoma cells via modulation of the NF-κB pathway. Together, these findings show that the HBeAg inhibits IL-18 signaling and IFN-γ expression, which may play an important role in the establishment and/or maintenance of persistent HBV infection.

Original languageEnglish
Pages (from-to)10412-10420
Number of pages9
JournalJournal of Virology
Volume88
Issue number18
DOIs
Publication statusPublished - 2014

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Jegaskanda, S., Ahn, S. H., Skinner, N., Thompson, A. J., Ngyuen, T., Holmes, J., de Rose, R., Navis, M., Winnall, W. R., Kramski, M., Bernardi, G., Bayliss, J., Colledge, D., Sozzi, V., Visvanathan, K., Locarnini, S. A., Kent, S. J., & Revill, P. A. (2014). Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen. Journal of Virology, 88(18), 10412-10420. https://doi.org/10.1128/JVI.00111-14