Hepatitis B virus genome replication triggers toll-like receptor 3-dependent interferon responses in the absence of hepatitis B surface antigen.
The hepatitis B virus (HBV) has been described as stealth virus subverting immune responses initially upon infection. Impaired toll-like receptor signaling by the HBV surface antigen (HBsAg) attenuates immune responses to facilitate chronic infection. This implies that HBV replication may trigger host innate immune responses in the absence of HBsAg. Here we tested this hypothesis, using highly replicative transgenic mouse models. An HBV replication-dependent expression of antiviral genes was exclusively induced in HBsAg-deficient mice. These interferon responses attributed to toll-like receptor 3 (TLR3)-activated Kupffer and liver sinusoidal endothelial cells and further controlled the HBV genome replication. However, activation of TLR3 with exogenous ligands indicated additional HBs-independent immune evasion events. Our data demonstrate that in the absence of HBsAg, hepatic HBV replication leads to Tlr3-dependent interferon responses in non-parenchymal liver cells. We hypothesize that HBsAg is a major HBV-mediated evasion mechanism controlling endogenous antiviral responses in the liver. Eradication of HBsAg as a therapeutic goal might facilitate the induction of endogenous antiviral immune responses in patients chronically infected with HBV.
Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Catherine Isabell
CI
Real
Institute of Virology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Mengji
M
Lu
Institute of Virology, University Hospital at the University Duisburg-Essen, Essen, Germany.|Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jia
J
Liu
Institute of Virology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Xuan
X
Huang
Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Martin
M
Trippler
Roche Kulmbach GmbH, Kulmbach, Germany.|Axolabs GmbH, Kulmbach, Germany.
Markus
M
Hossbach
Roche Kulmbach GmbH, Kulmbach, Germany.|Axolabs GmbH, Kulmbach, Germany.
Jochen
J
Deckert
Roche Kulmbach GmbH, Kulmbach, Germany.|Sanofi-Aventis Deutschland GmbH, Nucleic Acid Therapeutics Frankfurt, Germany.
Kerstin
K
Jahn-Hofmann
Roche Kulmbach GmbH, Kulmbach, Germany.|Boehringer Ingelheim Pharma GmbH Biberach, Biberach an der Riß, Germany.
Ludger Markus
LM
Ickenstein
Roche Kulmbach GmbH, Kulmbach, Germany.|Moderna Therapeutics, Cambridge, Massachusetts, USA.
Matthias Johannes
MJ
John
Institute of Virology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Kathrin
K
Gibbert
Institute of Virology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Ulf
U
Dittmer
Roche Kulmbach GmbH, Kulmbach, Germany.|Axolabs GmbH, Kulmbach, Germany.
Hans-Peter
HP
Vornlocher
Department of Internal Medicine, University Hospital at the University of Ulm, Ulm, Germany.
Reinhold
R
Schirmbeck
Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Guido
G
Gerken
Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.|Evangelisches Klinikum Niederrhein gGmbH, Duisburg, Germany.
Joerg Friedrich
JF
Schlaak
Department of Gastroenterology and Hepatology, University Hospital at the University Duisburg-Essen, Essen, Germany.
Ruth
R
Broering
D000818:Animals; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D007372:Interferons / Q000037:antagonists & inhibitors*; D051379:Mice; D008822:Mice, Transgenic; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors*; D014779:Virus Replication
D006514:Hepatitis B Surface Antigens; D051196:Toll-Like Receptor 3; D007372:Interferons