Immunorecognition and vesicular transfer of HDV RNA

• Applicant: Professorin Dr. Stephanie Jung
• Subject Area: Immunology ; Virology
• Term: since 2022
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506550754

Hepatitis D virus (HDV) infection is a global health problem affecting more than 15 million chronically infected patients living at high risk to develop severe fulminant hepatitis with high mortality rates. However, no curative treatment against chronic HBV-HDV infection is available so far. Despite of this urgent need for new therapies, the interaction of HDV with the innate immune system is only poorly understood. Recently, it has been shown that Melanoma Differentiation-Associated Protein 5 (MDA5) as a receptor of the innate immune system is responsible for the recognition of HDV infection and a resulting cytokine release. However, it is still unknown which HDV-associated RNAs are recognized by MDA5. Consequently, we aim at identifying immune-activating RNAs in HDV infection. Therefore, we’ll isolate MDA5-bound RNAs from HDV-infected and HDV-replicating cells and identify these RNAs in next-generation sequencing (aim 1). Subsequently, the immunostimulatory properties of these RNAs will be verified by stimulating primary immune cells and reporter systems. The resulting findings should lead to a better understanding of HDV-mediated immune activation, which is responsible for severe and often fatal courses of HDV infection, in order to enable the development of new diagnostic and therapeutic procedures. In the context of novel diagnostic developments, the promising and innovative field of extracellular vesicles (EVs) shows great potential. Since EVs play an important role in immunorecognition and pathogenesis of viral infections, we will investigate their impact on HDV recognition and the resulting immune responses. We will purify EVs released from HDV-infected cells in vitro and characterize their RNA content (aim 2). In particular, we want to determine which EV-encapsidated RNAs are responsible for the activation of non-infected immune cells by HDV-induced EVs. In the further course of the project, we will investigate which RNA sequences are also found in EVs purified from plasma of chronically HDV-infected patients (aim 3). In summary, the project proposed here will investigate RNA- and EV-mediated immune recognition of HDV infection, contributing to a better understanding of this fatal disease.

• DFG Programme: Research Grants