Innate Immune Responses in Hepatitis E Virus Infection in the Context of Liver Transplantation

• Applicant: Privatdozent Dr. Jens Martin Werner
• Subject Area: General and Visceral Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 463450560

The hepatitis E virus (HEV) is worldwide a common cause of acute viral hepatitis. Although acute HEV infections are most often self-limiting, there are some clinically relevant exceptions. Infection with genotype 1 during pregnancy may lead to up to 30% mortality. In immunosuppressed patients, such as organ transplant recipients, infection with HEV genotype 3 can cause chronic hepatitis and subsequent liver cirrhosis. A recent study reported a rate of 20% HEV infections in liver transplant (LTx) recipients undergoing liver biopsy for elevated liver enzymes and suspected acute rejection.Due to the recent increase in the frequency of acute HEV infection especially in immunocompromised patients, such as solid organ transplant recipients, humoral immunity and B-cell epitopes against HEV have been extensively studied, leading to highly improved detection assays. However, the role of innate cellular immune responses during HEV infection has not been studied in detail.In close collaboration with Prof. Dr. med. Jürgen J. Wenzel from the Institute of Clinical Microbiology and Hygiene at the University of Regensburg, we established in our laboratory an in vitro HEV infection system using the human hepatoma cell lines PLC/PRF/5 and Huh-7. This new model has the major advantage that a wild-type virus is used for infection, instead of an artificial plasmid construct with a subgenomic clone, as used in many previous studies.The main purpose of this study is to analyze innate immune cells with respect to their anti-viral immunity and their role in HEV infection, especially in liver transplant recipients. First, we will assess the effector functions of innate NK cells in the context of HEV replication and to identify receptor ligand interactions that facilitate NK cell cytotoxicity in vitro. Next, we will examine the effect of immunosuppression and antivirals such as RBV on NK cells in the context of in vitro HEV infection. Then, we will determine if evidence of activation of innate immune cells is detected in serum and liver biopsies of acute HEV-infected patients and LTx recipients. Finally, we will prospectively investigate NK cell activation and function in the course of HEV infection and during RBV therapy.In summary, with our experimental plans, we will be able to characterize innate NK cell responses in the context of a HEV infection in vitro and ex vivo in LTx recipients. These observations might help to explain the limited durability of immune responses against HEV and lead new approaches to guide HEV treatment in LTx recipients.

• DFG Programme: Research Grants