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Transcriptomic analysis of the woodchuck model of chronic hepatitis B
Author(s) -
Fletcher Simon P.,
Chin Daniel J.,
Ji Yongmei,
Iniguez A. Leonardo,
Taillon Bruce,
Swinney David C.,
Ravindran Palanikumar,
Cheng Donavan T.,
Bitter Hans,
Lopatin Uri,
Ma Han,
Klumpp Klaus,
Menne Stephan
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25730
Subject(s) - woodchuck hepatitis virus , hepatocellular carcinoma , virology , transcriptome , hepatitis b virus , biology , interferon , virus , immunology , hepadnaviridae , medicine , cancer research , gene , gene expression , genetics
The Eastern woodchuck ( Marmota monax ) is naturally infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to the human hepatitis B virus (HBV). The woodchuck is used as an animal model for studying chronic hepatitis B (CHB) and HBV‐associated hepatocellular carcinoma (HCC) in humans, but the lack of sequence information has hitherto precluded functional genomics analysis. To address this major limitation of the model, we report here the sequencing, assembly, and annotation of the woodchuck transcriptome, together with the generation of custom woodchuck microarrays. Using this new platform, we characterized the transcriptional response to persistent WHV infection and WHV‐induced HCC. This revealed that chronic WHV infection, like HBV, is associated with (1) a limited intrahepatic type I interferon response; (2) intrahepatic induction of markers associated with T cell exhaustion; (3) elevated levels of suppressor of cytokine signaling 3 (SOCS3) in the liver; and (4) intrahepatic accumulation of neutrophils. Underscoring the translational value of the woodchuck model, this study also determined that WHV‐induced HCC shares molecular characteristics with a subtype of human HCC with poor prognosis. Conclusion: Our data establish the translational value of the woodchuck model and provide new insight into immune pathways which may play a role either in the persistence of HBV infection or the sequelae of CHB. (H EPATOLOGY 2012;56:820–830)