These authors contributed equally to this work. Dr. Yongmei Ji is currently affiliated with University of Chicago Booth School of Business, Chicago, IL; Dr. Bruce Taillon is currently affiliated with Enzo Life Sciences, Farmingdale, NY; Dr. David C. Swinney is currently affiliated with iRND3, Institute for Rare and Neglected Diseases Drug Discovery, Belmont, CA; Dr. Simon Fletcher and Dr. Uri Lopatin are currently affiliated with Gilead Science, Foster City, CA.
Article first published online: 12 JUL 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 3, pages 820–830, September 2012
How to Cite
Fletcher, S. P., Chin, D. J., Ji, Y., Iniguez, A. L., Taillon, B., Swinney, D. C., Ravindran, P., Cheng, D. T., Bitter, H., Lopatin, U., Ma, H., Klumpp, K. and Menne, S. (2012), Transcriptomic analysis of the woodchuck model of chronic hepatitis B. Hepatology, 56: 820–830. doi: 10.1002/hep.25730
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.
- Issue published online: 28 AUG 2012
- Article first published online: 12 JUL 2012
- Accepted manuscript online: 20 MAR 2012 12:00AM EST
- Manuscript Accepted: 6 MAR 2012
- Manuscript Received: 24 JAN 2012
- College of Veterinary Medicine, Cornell University. Grant Number: N01-AI-05399
- National Institute of Allergy and Infectious Diseases (NIAID)
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)