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Dao Thi Lab
We study hepatitis E virus-host interactions using stem cell-derived culture systems

ABOUT US

CIID building

We are an international team of scientists who enjoy studying viruses. We use stem cell-derived culture systems to study hepatitis E virus-host interactions.

Our lab is a part of the Center of Integrative Infectious Disease Research (CIID) at the Heidelberg University Hospital. Our research is generously supported by the Chica and Heinz Schaller Foundation.

Uni klinikum
CHS foundation

WHO WE ARE

Loan
Viet Loan
Dao Thi, PhD

Principal Investigator

x Loan

After completing her dual studies in Biotechnology at the Technische Universität Berlin (Germany) and Dongseo University in Busan (South Korea), Loan received her PhD from the École Normale Supérieure in Lyon (France) where she trained with Prof. François-Loïc Cosset. She then pursued her interest in virology during two complementary postdoctoral phases in the labs of Prof. Darius Moradpour at the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) and Prof. Charles M. Rice at the Rockefeller University in New York (USA).

In 2018, Loan returned to Germany to join the Virology department at Heidelberg University Hospital as a Chica and Heinz Schaller Junior Research Group Leader.

When not doing science, Loan likes to travel and hike.

Andrew
Andrew
Freistaedter, MSc

Lab manager

x Andrew

Andrew grew up in "The South" of the U.S., getting his Master's degree in North Carolina. As of 2017, he has been living in Germany, getting a feel for the European lifestyle.

Charlotte
Rebecca
Fu, MSc

PhD student

x Rebecca

Rebecca is from Canada and did her BSc in Biotechnology at the University of British Columbia in Vancouver. She then did her MSc Infectious Diseases at University of Edinburgh in Scotland and worked during her Master thesis on Herpes Simplex Virus-1 viral entry. After the MSc, she worked as a research assistant at University of Edinburgh and did research on HIV-1 restriction factors.

Since February 2018, Rebecca joined the lab for her PhD studies on HEV host interactions.

Outside the lab she enjoys baking, reading, hiking and going to the gym.

Charlotte
Charlotte
Decker, MSc

PhD student

x Charlotte

Charlotte finished her Master’s degree in Molecular Biotechnology in Heidelberg. She is now working as a PhD student on hepatitis E virus trafficking.

In her leisure time she enjoys reading and swimming.

Cindy
Cindy
Zhang

MD student

x Cindy

Cindy is a medical student at the University of Heidelberg and currently working on a RNAi and Adeno-associated Virus vector based gene therapy approach against Hepatitis E. Her MD Thesis is a collaborative project between the Grimm Lab and the Dao Thi lab and supported by a DZIF fellowship.

Outside of the lab she enjoys acting, literature and traveling to foreign places.

Lars
Lars
Maurer

MD student

x Lars

Lars is a medical student at the University of Heidelberg. His MD thesis, supported by the SFB1129, is a collaboration between the Dao Thi lab and the Grimm lab. In his project Lars is exploring AAV-based expression of HEV capsid as a novel vaccine candidate.

In his free time, he enjoys going to the gym and meeting friends.

OUR WORK

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 ~60'000 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; Figure 1).

Figure 1: Differentiation of human pluripotent stem cells (embryonic or induced, hESC/iPSCs) to hepatocyte-like cells (HLCs; Wu & Dao Thi et al. 2018, Gastroenterology).

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 2).

Figure 2: Stem cell culture models of HEV infection. Cells collected from identified HEV positive individuals can be reprogrammed to generate iPSCs. Relevant SNPs can be repaired or introduced into established hESC/iPSC lines using CRISPR-Cas9, followed by differentiation to the cell type of interest. Differentiated cells can be directly infected with HEV isolates from patients or animals for modeling virus-host interactions in a dish (Dao Thi et al., 2018, Cold Spring Harb Perspect Med).

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 efforts should lead to a better understanding of HEV life cycle and host interactions with the overriding goal of developing new specific antiviral treatments.

Our work is funded by generous grants from different sources

CHS foundation

DZIF
SFB1129
TRR179

OPEN POSITIONS

We are searching for a PhD student to advance our studies on HEV-host interactions.

If you are highly motivated, interactive, and team-oriented with a background in molecular biology and/or virology and are interested in learning and applying a wide range of molecular and cell biological techniques to find out more about HEV, please contact us!

If you are interested in virology and stem cell technology, please apply. We are currently searching for MSc and PhD students.

This position has been filled

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

Hepatitis E virus (HEV) is the major cause of acute hepatitis in the world. Our lab uses stem cell technology to study HEV life cycle and HEV-host interaction. One particular aspect is HEV secretion, which is governed by its fecal-oral route transmission. The virus enters via the gastrointestinal tract and infects the liver, where it enters polarized hepatocytes from the bloodstream and exits with the bile to be shed into feces. We previously developed a novel differentiation protocol that allows columnar polarization of human embryonic or induced pluripotent stem cell (hESC/iPSC)-derived hepatocyte-like cells (HLCs) in transwells. Polarized HLCs can be infected with HEV on their basal side, with the majority of infectious virus being released to the apical compartment, recapitulating the directionality of infection occurring in vivo.

The successful applicant will combine this novel polarity system with genetic, biochemical, and imaging approaches to identify and characterize polarized trafficking and secretion routes of HEV. These efforts may help develop new strategies to block HEV assembly and secretion. Beyond virology, this work may lead to a better understanding of the fine-tuned spatio-temporal dynamics and regulation of the polarized trafficking machinery in hepatocytes.

Methods that will be used:
A wide range of molecular and cell biological techniques with emphasis on live cell imaging using confocal microscopy; human tissue culture including embryonic and induced pluripotent stem cells and their differentiation to various cell types, mainly hepatocytes; 3D and complex co-culture systems; infection studies with human viruses in BSL2 and potentially BSL3 laboratories.

Personal qualifications:
We are looking for a highly motivated, interactive and team-oriented candidate with a background and interest in molecular biology and virology. Applicants should hold a Master’s degree in Biomedical or Molecular Sciences, Biochemistry, Biology or related fields. Expertise in cell imaging and confocal microscopy is advantageous.

Please apply through the Heidelberg Biosciences International Graduate School (HBIGS).

SELECTED PUBLICATIONS

    2019
  • Fu RM, Decker CC, Dao Thi VL (2019). Cell Culture Models for Hepatitis E Virus. Viruses. 11:608 Viruses
  • Wang J,Qu B,Zhang F,Zhang C, Deng W, Dao Thi VL, Xia Y (2019). Stem Cell-Derived Hepatocyte-Like Cells as Model for Viral Hepatitis Research. Stem Cells International. 2019:9605252 Stem Cells International
  • 2018
  • Dao Thi VL, Wu X, Rice CM (2018). Stem cell-derived culture models of hepatitis E virus infection. Cold Spring Harbor Perspectives in Medicine. a031799 Pubmed
  • Wu X*, Dao Thi VL*, Liu P, Takacs CN, Xiang K, Andrus L, Gouttenoire J, Moradpour D, Rice CM (2018). Pan-Genotype Hepatitis E Virus Replication in Stem Cell-Derived Hepatocellular Systems. Gastroenterology. 154:663-674 Pubmed
  • Todt D, Moeller N, Praditya D, Kinast V, Friesland M, Engelmann M, Verhoye L, Sayed IM, Behrendt P, Dao Thi VL et al. (2018). The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo. Antiviral Research. 157:151-158 Pubmed
  • Knegendorf L, Drave SA, Dao Thi VL, Debing Y, Brown RJP, Vondran FWR, Resner K, Friesland M, Khera T, Engelmann M et al. (2018). Hepatitis E virus replication and interferon responses in human placental cells. Hepatology Communications. 2:173-187 Pubmed
  • Wu X, Dao Thi VL, Huang Y, Billerbeck E, Saha D, Hoffmann H-H, Wang Y, Vale Silva LA, Sarbanes S, Sun T et al. (2018). Intrinsic immunity shapes viral resistance of stem cells. Cell. 172:423-438 Pubmed
  • Chung H, Calis JJA, Wu X, Sun T, Yu Y, Sarbanes SL, Dao Thi VL, Shilvock AR, Hoffmann HH, Rosenberg BR et al. (2018). Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell. 172:811-824 Pubmed
  • Earlier papers
  • Takacs CN, Andreo U, Dao Thi VL, Wu X, Gleason CE, Itano MS, Spitz-Becker GS, Belote RL, Hedin BR, Scull MA et al. (2017). Differential regulation of lipoprotein and hepatitis C virus secretion by Rab1b. Cell Reports. 21:431-441 Pubmed
  • Dao Thi VL, Debing Y, Wu X, Rice CM, Neyts J, Moradpour D, Gouttenoire J (2016). Sofosbuvir inhibits hepatitis E virus replication in vitro and results in an additive effect when combined with ribavirin. Gastroenterology. 150:82-85 Pubmed
  • Hiroz P, Gouttenoire J, Dao Thi VL, Doerig C, Moradpour D, Sahli R, Telenti A (2013). Mise à jour sur l’hépatite E. Revue Médicale Suisse. 9:1594-1598 Journal website
  • Molina-Jimenez F, Benedicto I, Dao Thi VL Gondar V, Lavillette D, Marin JJ, Briz O, Moreno-Otero R, Aldabe R, Baumert TF, Cosset FL, Lopez-Cabrera M, Majano PL (2012). Matrigel-embedded 3D culture of Huh-7 cells as a hepatocyte-like polarized system to study hepatitis C virus cycle. Virology. 425:31-39 Pubmed

LAB NEWS

July 2019: Rebecca and Charlotte's review paper accepted at Viruses

June 2019: The lab participated in the BASF Firmencup race
June 2019: The lab participated in the BASF Firmencup race
June 2019: The lab participated in the BASF Firmencup race

May 2019: Lars started his MD thesis in the lab

Feb 2019: The lab attended the 1st Essen Hepatitis E meeting
Feb 2019: Cindy gave a talk at the 1st Essen Hepatitis E meeting

Feb 2019: First group photo


Feb 2019: Charlotte and Rebecca joined the lab as our first PhD students

Dec 2018: First Christmas dinner
Dec 2018: First Christmas dinner
Dec 2018: First Christmas dinner
Dec 2018: First Christmas dinner

CONTACT

Loan

Viet Loan Dao Thi, PhD
Junior Group Leader

Center for Integrative Infectious Disease Research (CIID)
University Hospital Heidelberg
Im Neuenheimer Feld 344
D-69120 Heidelberg, Germany

+49 (0) 6221 563 56 43

VietLoan.DaoThi {at} med.uni-heidelberg.de