Transcriptomic analysis of the woodchuck model of chronic hepatitis B§

Authors


  • Potential conflict of interest: A. Leonardo Iniguez is an employee of Roche NimbleGen, the corporation which generated (and may commercialize) the custom woodchuck microarray. Dr. Fletcher is employed by Roche. Dr. Chin is employed by and owns stock and intellectual property rights in Roche. Dr. Taillon is employed by Roche. Dr. Chen is employed by Roche. Dr. Ma is employed by Roche. Dr. Klumpp is employed by Roche.

  • The complete woodchuck transcriptome data are available at the NCBI SRA under accession number SRA050380 and the microarray data have been deposited in the NCBI GEO under accession number GSE36250.

Abstract

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. (HEPATOLOGY 2012;56:820–830)

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