Analysis of host responses to hepatitis B and delta viral infections in a micro-scalable hepatic co-culture system.

TitleAnalysis of host responses to hepatitis B and delta viral infections in a micro-scalable hepatic co-culture system.
Publication TypeJournal Article
Year of Publication2019
AuthorsWiner, BY, Gaska, JM, Lipkowitz, G, Bram, Y, Parekh, A, Parsons, L, Leach, R, Jindal, R, Cho, CH, Shrirao, A, Novik, E, Schwartz, RE, Ploss, A
JournalHepatology
Date Published2019 Jun 17
ISSN1527-3350
Abstract

Hepatitis B virus (HBV) remains a major global health problem with 257 million chronically infected individuals worldwide, of whom approximately 20 million are co-infected with hepatitis delta virus (HDV). Progress towards a better understanding of the complex interplay between these two viruses and development of novel therapies have been hampered by the scarcity of suitable cell culture models that mimic the natural environment of the liver. Here, we established HBV and HBV/HDV co- and super-infections in self-assembling co-cultured primary human hepatocytes (SACC-PHHs) for up to 28 days in a 384 well format and highlight the suitability of this platform for high-throughput drug testing. We performed RNAseq at days 8 and 28 on SACC-PHHs either HBV mono- or HBV/HDV co-infected. Our transcriptomic analysis demonstrates that hepatocytes in SACC-PHHs maintain a mature hepatic phenotype over time regardless of infection condition. We confirm that HBV is a stealth virus as it does not induce a strong innate immune response; rather oxidative phosphorylation and extracellular matrix-receptor interactions are dysregulated to create an environment that promotes persistence. Notably, HDV co-infection also did not lead to statistically significant transcriptional changes across multiple donors and replicates. The lack of innate immune activation is not due to SACC-PHHs being impaired in their ability to induce interferon stimulated genes (ISGs). Rather poly(I:C) exposure activates ISGs and that this stimulation significantly inhibits HBV infection but only minimally affects the ability of HDV to infect and persist. Altogether, these data demonstrate that the SACC-PHH system is a versatile platform for studying HBV/HDV co-infections and holds promise for performing chemical library screens and improving our understanding the host response to such infections. This article is protected by copyright. All rights reserved.

DOI10.1002/hep.30815
Alternate JournalHepatology
PubMed ID31206195
Grant ListK08 DK101754 / DK / NIDDK NIH HHS / United States
R03 DK117252 / DK / NIDDK NIH HHS / United States