Investigators Discover How Hepatitis E Virus Infiltrates Cells

Despite causing approximately 20 million infections every year, hepatitis E virus is relatively understudied. A robust cell model of the virus was first produced 3 years ago, and investigators are just beginning to understand how hepatitis E infiltrates the body.

The entry process of hepatitis E viral particles may be a target for early and aggressive pharmaceutical intervention. However, druggable host factors to hinder hepatitis E entry had yet to be identified.

A new study, published in Hepatology, identified the epidermal growth factor receptor (EGFR) as a novel host factor for hepatitis E infection. The research also exposed the significance of EGFR for the hepatitis E viral entry process.

The investigators discovered EGFR was critical for hepatitis E infection after utilizing RNAi, ectopic expression of EGFR, and chemical modulation with drugs approved by the US Food and Drug Administration (FDA). These strategies enabled the scientists to discover the essential role of EGFR without affecting hepatitis E RNA replication or assembly of the progeny virus.

“We used drugs to suppress the activity of the EGFR protein in some cell lines at the time of virus entry,” said Jil Alexandra Schrader, the first author of the study. “In these cultures, we observed that there were significantly fewer infected cells.”

The investigators found it is not the signaling function of EGFR that causes the proviral effect, but the ligand binding domain of EGFR itself. Hepatitis E viral infection was affected by the modulation of epidermal growth factor expression in HepaRG cells, as well as by primary human hepatocytes.

To confirm their findings, the investigators used cell cultures with an overproduced coreceptor. In these models, 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,” Schrader said.

When the protein was missing, the hepatitis E virus could not penetrate the cell. “Taken together,” the investigators concluded, “our study provides novel insights into the life cycle of hepatitis E virus and identified EGFR as a possible target for future antiviral strategies against HEV.” They recommended further study to determine whether other factors are needed for hepatitis E to enter cells, or if the receptor itself admits the virus.

These findings are important, especially because there are already drugs that target the epidermal growth factor receptor. The US and Europe have authorized drugs for certain cancers that specifically target overactive receptors that can trigger uncontrolled cell growth.

Hepatitis E virus is the most common cause of acute viral hepatitis. Of the global 20 million hepatitis E viral infections, about 3.3 million are symptomatic and 70000 become fatal. The first documented hepatitis E viral outbreak occurred in 1955-1956, but the virus would not be deeply studied for half a century.

In individuals with an adequate immune system, most hepatitis E infections resolve untreated. However, in immunosuppressed persons, hepatitis E can become chronic. The virus is especially dangerous in individuals who are pregnant, living with HIV, or organ transplant recipients.