EGF receptor modulates HEV entry in human hepatocytes

Background and Aims: Being the most common cause of acute viral hepatitis with >20 million cases per year and 70,000 deaths annually, HEV presents a long-neglected and underinvestigated 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 EGF 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 Food and Drug Administration-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 and 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 antiviral strategies against HEV.

Automated summary

This study identified the EGF receptor (EGFR) as a novel host factor for HEV and revealed the significance of EGFR for the HEV entry process. It was found that EGFR itself and its ligand-binding domain, rather than its signaling function, is responsible for the proviral effect. These findings provide new insights into the life cycle of HEV and identify EGFR as a potential target for future antiviral strategies against HEV.