Robust hepatitis E virus infection and transcriptional response in human hepatocytes.
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Authors
Todt, DanielFriesland, Martina
Moeller, Nora
Praditya, Dimas
Kinast, Volker
Brüggemann, Yannick
Knegendorf, Leonard
Burkard, Thomas
Steinmann, Joerg
Burm, Rani
Verhoye, Lieven
Wahid, Avista
Meister, Toni Luise
Engelmann, Michael
Pfankuche, Vanessa M
Puff, Christina
Vondran, Florian W R
Baumgärtner, Wolfgang
Meuleman, Philip
Behrendt, Patrick
Steinmann, Eike
Issue Date
2020-01-02
Metadata
Show full item recordAbstract
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and the leading cause for acute viral hepatitis worldwide. The virus is classified as a member of the genus Orthohepevirus A within the Hepeviridae family. Due to the absence of a robust cell culture model for HEV infection, the analysis of the viral life cycle, the development of effective antivirals and a vaccine is severely limited. In this study, we established a protocol based on the HEV genotype 3 p6 (Kernow C-1) and the human hepatoma cell lines HepG2 and HepG2/C3A with different media conditions to produce intracellular HEV cell culture-derived particles (HEVcc) with viral titers between 105 and 106 FFU/mL. Viral titers could be further enhanced by an HEV variant harboring a mutation in the RNA-dependent RNA polymerase. These HEVcc particles were characterized in density gradients and allowed the trans-complementation of subgenomic reporter HEV replicons. In addition, in vitro produced intracellular-derived particles were infectious in liver-humanized mice with high RNA copy numbers detectable in serum and feces. Efficient infection of primary human and swine hepatocytes using the developed protocol could be observed and was inhibited by ribavirin. Finally, RNA sequencing studies of HEV-infected primary human hepatocytes demonstrated a temporally structured transcriptional defense response. In conclusion, this robust cell culture model of HEV infection provides a powerful tool for studying viral-host interactions that should facilitate the discovery of antiviral drugs for this important zoonotic pathogen.Citation
Proc Natl Acad Sci U S A. 2020 Jan 2. pii: 1912307117. doi: 10.1073/pnas.1912307117.Affiliation
TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.Publisher
National Academy of SciencesPubMed ID
31896581Type
ArticleLanguage
enISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1912307117
Scopus Count
The following license files are associated with this item:
- Creative Commons
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