title: Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen.
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.
  
  
  OBJECTIVE
  It is becoming increasingly apparent that NK cells play a role in the establishment and/or maintenance of chronic hepatitis B infection. The secreted HBeAg is an important regulator of innate and adaptive immune responses. We now show that the HBeAg downregulates NK cell-mediated IFN-γ production and IL-18 signaling, which may contribute to the establishment of infection and/or viral persistence. Our findings build on previous studies showing that the HBeAg also suppresses the TLR and IL-1 signaling pathways, suggesting that this viral protein is a key regulator of antiviral innate immune responses.
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Jegaskanda
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Medicine, Eastern Hill Academic Centre, The University of Melbourne, Parkville, Victoria, Australia Department of Infectious Diseases, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Skinner
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia Department of Medicine, Eastern Hill Academic Centre, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Ngyuen
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Holmes
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: De Rose
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Navis
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: W R
authors.initials: WR
authors.lastname: Winnall
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Kramski
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Bernardi
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Bayliss
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Colledge
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Sozzi
authors.affiliation: Department of Medicine, Eastern Hill Academic Centre, The University of Melbourne, Parkville, Victoria, Australia Department of Infectious Diseases, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Visvanathan
authors.affiliation: Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Locarnini
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Kent
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Parkville, Victoria, Australia Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia peter.revill@mh.org.au.
authors.forename: P A
authors.initials: PA
authors.lastname: Revill
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D006509:Hepatitis B / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D006513:Hepatitis B e Antigens; D020382:Interleukin-18; D007371:Interferon-gamma