Research group Dao Thi

Research projects in our group focus on "Hepatitis E Virus-Host Interactions using Stem Cell-Derived Culture Systems".

Projects

The Dao Thi lab uses stem cell-derived culture models to study hepatitis E virus (HEV). With about 20 million infections each year, leading to more than 3 million symptomatic cases and ~60000 fatalities, HEV is believed to be the most common cause of acute hepatitis in the world. Despite increasing awareness, HEV remains an understudied virus. A contributor to the poor understanding is the difficulty to propagate HEV in cell culture. To overcome these limitations, we use embryonic or induced pluripotent stem cell (hESC/iPSC)-derived cell culture models, in particular stem-cell derived hepatocyte-like cells (HLCs). Unlike conventionally used hepatoma cells, we found that HLCs are permissive for infection by primary isolates of all four HEV genotypes that can infect humans. HLCs therefore enable studies of authentic pan-genotype HEV biology. Further, the capability to study replication of non-adapted HEV isolates in tandem with autologous, patient-derived iPSCs enables personalized models of HEV infection and will serve as a platform for testing novel anti-HEV treatments (Figure 1).

We also developed a novel stem cell-based differentiation protocol that uses transwell filters to generate columnar polarized HLCs. HEV is transmitted via the fecal-oral route and hepatocytes are similar to other epithelial cells polarized in vivo. In the absence of robust hepatocyte polarity systems our polarized HLC system now allows us to study directional HEV assembly and release, the final steps of the virus life cycle. Our studies aim at understanding different steps of the HEV life cycle with the overriding goal to identify new specific targets for therapeutic intervention.