title: Transcriptomic analysis of the woodchuck model of chronic hepatitis B.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hoffmann-La Roche, Nutley, NJ, USA. Simon.Fletcher@gilead.com
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fletcher
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Chin
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Ji
authors.forename: A Leonardo
authors.initials: AL
authors.lastname: Iniguez
authors.forename: Bruce
authors.initials: B
authors.lastname: Taillon
authors.forename: David C
authors.initials: DC
authors.lastname: Swinney
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Ravindran
authors.forename: Donavan T
authors.initials: DT
authors.lastname: Cheng
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.forename: Uri
authors.initials: U
authors.lastname: Lopatin
authors.forename: Han
authors.initials: H
authors.lastname: Ma
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.forename: Stephan
authors.initials: S
authors.lastname: Menne
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000821:virology*; D008297:Male; D008392:Marmota; D059467:Transcriptome