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\begin{document}

\title{Assessment of HBV Infection and Inter-host Cellular Responses using
Intrahepatic Cholangiocyte Organoids}



\author[1]{Chuan Kok Lim}%
\author[2]{Ornella Romeo}%
\author[3]{Bang Manh Tran}%
\author[4]{Dustin Flanagan}%
\author[2]{Emily Kirby N}%
\author[5]{Erin McCartney}%
\author[5]{Edmund Tse}%
\author[1]{Elizabeth Vincan}%
\author[2]{Michael Beard}%
\affil[1]{Victorian Infectious Diseases Reference Laboratory Molecular and Research Development}%
\affil[2]{The University of Adelaide School of Computer and Mathematical Sciences}%
\affil[3]{The University of Melbourne Department of Anatomy and Physiology}%
\affil[4]{Monash University Monash Venom and Toxins Research Group}%
\affil[5]{Royal Adelaide Hospital Medication}%


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  \date{May 26, 2024}


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\begin{abstract}
\textbf{Background \& Aims:} Intrahepatic cholangiocyte organoids (ICOs)
model was evaluated for host differences in HBV infection, cellular
responses, antiviral and immunomodulator responses. \textbf{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-\selectlanguage{greek}α \selectlanguage{english}and viral
mimic (PolyI:C) were assessed. \textbf{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-\selectlanguage{greek}α \selectlanguage{english}and PolyI:C, HBV
infection in ICOs did not upregulate ISGs. \textbf{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.%
\end{abstract}%



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\verb`Lim et al JMV28975 resubmission 271023.doc`  available at \url{https://authorea.com/users/695522/articles/684177-assessment-of-hbv-infection-and-inter-host-cellular-responses-using-intrahepatic-cholangiocyte-organoids}

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