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Assessment of HBV Infection and Inter-host Cellular Responses using Intrahepatic Cholangiocyte Organoids
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  • Chuan Kok Lim,
  • Ornella Romeo,
  • Bang Manh Tran,
  • Dustin Flanagan,
  • Emily Kirby N,
  • Erin McCartney,
  • Edmund Tse,
  • Elizabeth Vincan,
  • Michael Beard
Chuan Kok Lim
Victorian Infectious Diseases Reference Laboratory Molecular and Research Development

Corresponding Author:[email protected]

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Ornella Romeo
The University of Adelaide School of Computer and Mathematical Sciences
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Bang Manh Tran
The University of Melbourne Department of Anatomy and Physiology
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Dustin Flanagan
Monash University Monash Venom and Toxins Research Group
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Emily Kirby N
The University of Adelaide School of Computer and Mathematical Sciences
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Erin McCartney
Royal Adelaide Hospital Medication
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Edmund Tse
Royal Adelaide Hospital Medication
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Elizabeth Vincan
Victorian Infectious Diseases Reference Laboratory Molecular and Research Development
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Michael Beard
The University of Adelaide School of Computer and Mathematical Sciences
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Abstract

Background & Aims: Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in HBV infection, cellular responses, antiviral and immunomodulator responses. Methods: 12 ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterised using histology, confocal and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma derived HBV (genotype B & C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, cccDNA, extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes (ISG)) to interferon-α and viral mimic (PolyI:C) were assessed. Results: ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor dependent drug-responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Conclusions: Human ICOs support HBV infection and replication with donor dependent variation in viral dynamics and cellular responses. These features can be utilised for development of personalised drug testing platform for antivirals.
03 Nov 2023Submitted to Journal of Medical Virology
03 Nov 2023Submission Checks Completed
03 Nov 2023Assigned to Editor
03 Nov 2023Review(s) Completed, Editorial Evaluation Pending
03 Nov 2023Editorial Decision: Accept