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

Research output: Contribution to journalArticle

34 Citations (Scopus)

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

Fingerprint

interleukin-18
Interleukin-18
Hepatitis B e Antigens
Hepatitis B virus
interferon-gamma
Interferon-gamma
Down-Regulation
antigens
interferons
Natural Killer Cells
Interferons
natural killer cells
cells
chronic hepatitis B
Chronic Hepatitis B
Virus Diseases
hepatoma
Virus Replication
virus replication
Hepatocellular Carcinoma

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

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. / Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen. In: Journal of Virology. 2014 ; Vol. 88, No. 18. pp. 10412-10420.
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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.",
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Jegaskanda, S, Ahn, SH, Skinner, N, Thompson, AJ, Ngyuen, T, Holmes, J, de Rose, R, Navis, M, Winnall, WR, Kramski, M, Bernardi, G, Bayliss, J, Colledge, D, Sozzi, V, Visvanathan, K, Locarnini, SA, Kent, SJ & Revill, PA 2014, 'Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen', Journal of Virology, vol. 88, no. 18, pp. 10412-10420. https://doi.org/10.1128/JVI.00111-14

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

In: Journal of Virology, Vol. 88, No. 18, 2014, p. 10412-10420.

Research output: Contribution to journalArticle

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T1 - Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen

AU - Jegaskanda, S.

AU - Ahn, S. H.

AU - Skinner, N.

AU - Thompson, A. J.

AU - Ngyuen, T.

AU - Holmes, J.

AU - de Rose, R.

AU - Navis, M.

AU - Winnall, W. R.

AU - Kramski, M.

AU - Bernardi, G.

AU - Bayliss, J.

AU - Colledge, D.

AU - Sozzi, V.

AU - Visvanathan, K.

AU - Locarnini, S. A.

AU - Kent, S. J.

AU - Revill, P. A.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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