Hepatitis E is a common disease. However, little is known about the life cycle of the virus. Now, researchers from the molecular and medical virology department at Ruhr University Bochum and Carl von Ossietzky University Oldenburg report the protein EGFR plays a decisive role in the penetration of virus particles in the cells.

The findings are published in Hepatology in a paper titled, “Epidermal growth factor receptor modulates hepatitis E virus entry in human hepatocytes,” and may lead to new treatment options against hepatitis E.

“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,” wrote the researchers. “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.”

The researchers identified the epidermal growth factor receptor (EGFR) as a novel host factor for HEV and revealed the significance of EGFR for the HEV entry process. By utilizing RNAi, chemical modulation with FDA-approved drugs and ectopic expression of EGFR, they revealed that EGFR is critical for HEV infection, without affecting HEV RNA replication or assembly of progeny virus.

“We used drugs to suppress the activity of the EGFR protein in some cell lines at the time of virus entry”, explained first author Jil Alexandra Schrader, a doctorate student at Ruhr University Bochum. “In these cultures, we observed that there were significantly fewer infected cells.” To cross-check this, the researchers used cell cultures in which the co-receptor was over-produced. In this case, more infections occurred than in untreated cells.

“This shows us that the protein EGFR is of great importance for the entry mechanism of the virus into the cells,” said Schrader. Moreover, the part of the protein that is on the outside of the cells and to which ligands bind is important for the entry of viruses. If it is missing, viruses cannot penetrate the cell. Further investigations are needed to determine whether other players are required for the virus to infect cells or whether the receptor itself introduces the virus. “For hepatitis C virus, for example, it is known that even more receptors are involved in the entry of the viruses into the cells,” explained Eike Steinmann, PhD, professor and head of the department of molecular and medical virology at Ruhr University Bochum. “This could also be the case with hepatitis E virus.”

The researchers believe the evidence that EGFR is involved in infection is particularly interesting because there are already approved drugs that suppress its activity.

“These drugs are approved in Europe and the United States for certain cancers where the receptor is overactive and can cause uncontrolled cell growth,” explained Volker Kinast, PhD, virologist at the Carl von Ossietzky University Oldenburg. Further studies will be needed to show whether these agents could be a treatment option against hepatitis E.

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