EGF receptor modulates HEV entry in human hepatocytes

Background and Aims: Being the most common cause for acute viral hepatitis with more than 20 million cases per year and 70 000 deaths annually, hepatitis E virus (HEV) presents a long neglected and under-investigated health burden. Although the entry process of viral particles is an attractive target for pharmacological intervention, druggable host factors to restrict HEV entry have not been identified so far.Approach and Results: Here we identify the epidermal growth factor receptor (EGFR) as a novel host factor for HEV and reveal the significance of EGFR for the HEV entry process. By utilizing RNAi, chemical modulation with FDA-approved drugs and ectopic expression of EGFR, we revealed that EGFR is critical for HEV infection, without affecting HEV RNA replication or assembly of progeny virus. We further unveiled that EGFR itself and its ligand binding domain rather than its signaling function is responsible for the proviral effect. Modulation of EGF expression in HepaRG cells as well as primary human hepatocytes affected HEV infection.Conclusions: Taken together, our study provides novel insights into the life cycle of HEV and identified EGFR as a possible target for future anti-viral strategies against HEV