2 | Investigation of the mechanism of innate immunity activation by HDV replication and the role of IFN response in HDV chronicity
In contrast to HBV, HDV infection induces profound innate immune response which is mediated by pattern recognition receptor MDA5 (Zhang, et al. 2018. J Hepatol. 69:25–35). MDA5 is a cytosol sensor usually recognizing long double strand RNA (dsRNA). However, unlike other RNA viruses, HDV replicates its RNA in the nucleus via a unique double-rolling-cycle mechanism without producing long dsRNA. Investigating the innate immune activation during HDV replication will provide important insights for understanding MDA5 mediated innate immune sensing of viral RNA. To this aim, we plan to: (i) identify the HDV RNA ligand recognized by MDA5; (ii) determine the subcellular location of MDA5-HDV RNA interaction; and (iii) elucidate the roles of host factors (LGP2, ADAR1, etc.) and viral factors (HDAg and HBV envelope proteins) in the process of innate immunity activation.
Long term persistence of HBV and HDV makes it challenging to develop curative therapies. Extracellular spreading pathways are important for persistence of both viruses and can be blocked by the entry inhibitor Myrcludex B. However, HDV can also propagate through cell division. Our work has proved that this cell division mediated HDV spread is very sensitive to IFN response (unpublished). In this project we aim to elucidate the mechanism of cell division mediated HDV spread with the focus of understanding the role of IFN response in this process. To this end, we intend to: (i) characterize cell division mediated HDV spread in different cell lines with or without IFN response; (ii) identify the IFN induced antiviral factors contributing the blockade of HDV spread during cell division; (iii) establish an in vitro model supporting both extracellular and cell division mediated HDV spread; and (iv) develop novel synergistic co-treatments by combing inhibitors targeting targeting extracellular HDV spread (MyrB, Lonafarnib, etc.) and cell division mediated HDV spread (IFN, TLR agonists, etc.).