Hepatitis E virus trafficking in polarized human pluripotent
stem cell-derived hepatocyte-like systems

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2nd funding period (2018 – 06/2022)

Project description – Summary – 3rd funding period

Hepatitis E virus (HEV) is a major cause of acute hepatitis in the world. HEV is principally transmitted through the fecal-oral route. The polarity of cells in involved tissues, i.e the gut (intestinal epithelial cells) and the liver (hepatocytes), plays a critical role in HEV transmission: Usually posing a barrier between the inside and outside of the body, both intestinal cells and hepatocytes have developed fine-tuned trafficking machineries to provide the uptake of nutrients on the one hand and the directional secretion of distinct cargoes on the other hand. In a simplified manner, HEV has to enter these cells from one side and leave from the other side. 

During the previous funding period, we established a novel polarized stem cell-derived hepatocyte culture system (Dao Thi et al. 2020, Nat Commun) and implemented suitable live-cell compatible labelling strategies to track HEV structural proteins ORF2 and 3 in polarized cells. In the third funding period, we will continue the characterization of polarized ORF3 trafficking and will expand our analysis to trafficking infectious and non-infectious HEV ORF2 capsid forms. By studying HEV directional secretion, we do not only want to identify critical pathways for therapeutic HEV intervention, but also aim at gaining a better understanding of the polarized trafficking machinery in general.

Hepatitis E virus life cycle and transmission.
From Fu RM, Decker CC, Dao Thi VL (2019). Cell Culture Models for Hepatitis E Virus. Viruses 11, 608; doi:10.3390/v11070608
Differentiation of human pluripotent stem cells to hepatocyte-like cells.
From Wu X, Dao Thi VL, Liu P, Takacs CN, Xiang K, Andrus L, Gouttenoire J, Moradpour D, Rice CM. Pan-Genotype Hepatitis E Virus Replication in Stem Cell-Derived Hepatocellular Systems. Gastroenterology 2018 Feb;154(3):663-674.e7. doi: 10.1053/j.gastro.2017.10.041. Epub 2017 Dec 24.

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