Role of interferon-stimulated genes during hepatitis E virus infection in human and swine (RIEHS)

• Applicants: Dr. Volker Kinast; Professor Dr. Eike Steinmann
• Subject Area: Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510558817

The hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in humans worldwide. Each year, estimated 20 million HEV infections occur, leading to approximately 3.3 million cases of acute illness and 70,000 HEV-related deaths. A reciprocal effect of interferon (IFN) and JAK-Inhibitors implies a critical role of the IFN response including interferon-stimulated genes (ISGs) to combat HEV infections in humans. However, the underlying molecular mechanism which ISGs contribute to the IFN-mediated restriction remains elusive. Moreover, their importance for virus tolerance in pigs, which are considered to be the virus reservoir, is completely undescribed. Therefore, the aim of this project is to analyze the influence of ISGs to control HEV infections in humans and pigs. We performed an arrayed ISG screen and pinpointed the critical human ISGs with anti-HEV activity. By utilizing virological, biochemical and genetic state-of-the-art techniques, we aim to unravel the mechanism-of-actions of an ISG with a strong anti-HEV phenotype. Due to the divergent course of HEV infection in humans and swine, we further hypothesize that HEV triggers a different innate immune response including species-specific patterns of ISG expression. Hence, analysis of the transcriptional response of HEV-infected primary porcine hepatocytes (PPHs) may contribute to understanding of the differential pathogenesis in humans and swine and further will help to generate a porcine ISG screen. This library will enable to elucidate the role of porcine ISGs to combat HEV infections. Similar to the human ISG screen, a porcine ISG with a strong anti-HEV phenotypes will be analyzed in detail. Moreover, it will help to determine species-specific restriction factors against HEV, on which we will pay special attention. The results of this project will not only contribute to the understanding of the role of ISGs to restrict HEV, but further to fundamental aspects of HEV virology and the mammalian innate immunity.

• DFG Programme: Research Grants