Primary supervisor: Prof. C. O`Farrelly, Trinity College Dublin, Ireland
Title: To determine the interaction between viral detection and innate immune responses in inducible pluripotent stem cell (iPSC)-derived hepatocytes from hepatitis C virus resistant individuals
Collaborators: Dr. A. Bergthaler, The Research Center for Molecular Medicine (CeMM), Vienna, Austria; Dr. R. Zahn, Janssen, Leiden, The Netherlands
Early Stage Researcher: Mihai Sularea
This study will exploit iPSCs generated from a unique cohort of Irish women who were exposed to Hepatitis-C virus (HCV) from a single source via contaminated anti-D in 1977-79 (anti-D cohort). The women who became infected are well studied, but up to 40% of the cohort with documented evidence of HCV-exposure have never shown clinical or immunological signs of infection and we hypothesize that this is due to a highly effective innate antiviral immune response, particularly in their hepatocytes. Through exclusive access to samples from virus resistant women of the anti-D cohort together with transfer of state-of-the-art stem-cell technologies from our collaborators in Edinburgh, we have a unique possibility to understand the role of innate immune signalling and immunometabolic activity in resistance to viral infection in iPSC derived hepatocytes and macrophages. Since innate immune pathways are not pathogen-specific, we propose that the identification of mechanisms of HCV-resistance by this study will apply to other Flavi-viruses including Zika and Dengue viruses. ESR 13 will address the aim of this project by generation of hepatocytes (HLCs) from donor iPSCs, followed by viral-ligand stimulation and HCV infection of viral resistant and susceptible iPSC-derived hepatocytes. Next Gen sequencing of RNA from infected hepatocytes and metabolic analysis of pathways activated in viral resistant and susceptible cells, followed by validation by RT-PCR and Western blotting, will determine whether viral modulation of the immune signalling and immune-metabolic pathways plays a role in resistance to viral infections. In collaboration with Dr. Bergthaler in Vienna, ESR13 will analyse interferon-modulated hepatic metabolic pathways in viral resistant and viral sensitive iPSC induced hepatocytes and in collaboration with Dr. Zahn at Janssen in Leiden, the Netherlands, ESR13 will identify immunometabolism pathways that influence antiviral activity in iPSC derived hepatocytes.