Hepatitis B virus evasion from cGAS sensing in human hepatocytes.
Fiche publication
Date publication
avril 2018
Journal
Hepatology (Baltimore, Md.)
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas, Pr PESSAUX Patrick, Dr VERRIER Eloi
Tous les auteurs :
Verrier ER, Yim SA, Heydmann L, El Saghire H, Bach C, Turon-Lagot V, Mailly L, Durand SC, Lucifora J, Durantel D, Pessaux P, Manel N, Hirsch I, Zeisel MB, Pochet N, Schuster C, Baumert TF
Lien Pubmed
Résumé
Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic GMP-AMP synthase (cGAS) was identified as a DNA sensor. In this study, we aimed to investigate the functional role of cGAS in sensing of HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss- and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes and HBV-infected human liver chimeric mice. Here we show that cGAS is expressed in the human liver, primary human hepatocytes and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral cccDNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice.
Mots clés
Animals, Blotting, Western, Cell Culture Techniques, DNA, Viral, immunology, Gene Expression Profiling, methods, Hepatitis B, immunology, Hepatitis B virus, pathogenicity, Hepatocytes, metabolism, Host-Pathogen Interactions, Humans, Immune Evasion, immunology, In Situ Hybridization, Fluorescence, methods, Mice, Nucleotides, Cyclic, metabolism, Real-Time Polymerase Chain Reaction
Référence
Hepatology. 2018 Apr 20;: