title: Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection.
abstract: OBJECTIVE
  The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice.
  
  
  METHODS
  Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence.
  
  
  RESULTS
  Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-ß, hIFN-ß and hIFN-λ) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling.
  
  
  CONCLUSIONS
  Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes.
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Katja
authors: K
authors: Giersch
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Lena
authors: L
authors: Allweiss
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Tassilo
authors: T
authors: Volz
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Martina
authors: M
authors: Helbig
authors: Department for General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Germany.
authors: Jeanette
authors: J
authors: Bierwolf
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel Site, Germany.
authors: Ansgar W
authors: AW
authors: Lohse
authors: Department for General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Germany.
authors: Joerg M
authors: JM
authors: Pollok
authors: IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany.
authors: Joerg
authors: J
authors: Petersen
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel Site, Germany. Electronic address: m.dandri@uke.de.
authors: Maura
authors: M
authors: Dandri
authors: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Marc
authors: M
authors: Lütgehetmann
mesh_terms: D000818:Animals; D060085:Coinfection / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000150:complications / Q000276:immunology* / Q000821:virology; D019701:Hepatitis D, Chronic / Q000150:complications / Q000276:immunology* / Q000821:virology; D003698:Hepatitis Delta Virus / Q000235:genetics*; D022781:Hepatocytes / Q000473:pathology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D018121:Receptors, Cytokine / Q000378:metabolism; D019562:Viral Load
chemical_list: C104577:IP10-Mig receptor; D018121:Receptors, Cytokine
keywords: Chronic viral hepatitis; HBV; HDV; ISG; uPA mice