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Thomsen, M.K.* ; Nandakumar, R.* ; Stadler, D. ; Malo, A. ; Valls, R.M.* ; Wang, F.* ; Reinert, L.S.* ; Dagnaes-Hansen, F.* ; Hollensen, A.K.* ; Mikkelsen, J.G.* ; Protzer, U. ; Paludan, S.R.*

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection.

Hepatology 64, 746-759 (2016)
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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 life time. HBV infects hepatocytes where it replicates its DNA and infection can lead to acute and chronic hepatitis with 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 I IFN production, and this occurs through a pathway dependent on the DNA sensor cGAS and the downstream adaptor protein STING. In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type I IFN in response to foreign DNA or HBV infection and mice lacking STING or cGAS 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 possess 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. In conclusion, 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gmp-amp Synthase; Hepatocellular-carcinoma; Factor-ix; Immune-response; Gene-expression; In-vivo; Interferon; Replication; Activation; Mice
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Journal Hepatology
Quellenangaben Volume: 64, Issue: 3, Pages: 746-759 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-502700-003
DOI 10.1002/hep.28685
WOS ID WOS:000383285900008
PubMed ID 27312012
Erfassungsdatum 2016-06-24
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