Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection.
Hepatitis B virus (HBV) is a major human pathogen, and about one third of the global population will be exposed to the virus in their lifetime. HBV infects hepatocytes, where it replicates its DNA and infection can lead to acute and chronic hepatitis with a high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type 1 interferon (IFN) production; and this occurs through a pathway dependent on the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase and the downstream adaptor protein stimulator of IFN genes (STING). In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type 1 IFN in response to foreign DNA or HBV infection and mice lacking STING or cyclic guanosine monophosphate-adenosine monophosphate synthase exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possesses anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo.



The lack of a functional innate DNA-sensing pathway in hepatocytes hampers efficient innate control of HBV infection; this may explain why HBV has adapted to specifically replicate in hepatocytes and could contribute to the weak capacity of this cell type to clear HBV infection. (Hepatology 2016;64:746-759).
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
Martin K
MK
Thomsen
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
Ramya
R
Nandakumar
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.
Daniela
D
Stadler
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.
Antje
A
Malo
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.
Roser Marin
RM
Valls
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.
Fan
F
Wang
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
Line S
LS
Reinert
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.
Frederik
F
Dagnaes-Hansen
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.
Anne Kruse
AK
Hollensen
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
Jacob Giehm
JG
Mikkelsen
Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.
Ulrike
U
Protzer
Department of Biomedicine and, University of Aarhus, Aarhus, Denmark.|Aarhus Research Center for Innate Immunology, University of Aarhus, Aarhus, Denmark.
Søren R
SR
Paludan
D000256:Adenoviridae; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D019694:Hepatitis B, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D007372:Interferons / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009713:Nucleotidyltransferases / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D007372:Interferons; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase