Frog cells offer clues to targetable ‘escape hatch’ for hepatitis E virus

Cells from the African clawed frog help explain how hepatitis E virus particles spread throughout the body.

Hepatitis E is a liver virus that causes 20 million infections a year, mostly in East and South Asia, according to the World Health Organization (WHO). The virus is primarily spread through contaminated food and water, but lately it’s been on the rise in Europe, where it’s believed to be caused by the consumption of undercooked meat.

There is no therapy that specifically attacks the E strain of the virus, but now researchers led by Princeton have found a clue that could lead to a targeted treatment.

The research team discovered that when hepatitis E infects cells, it makes “viroporins,” or proteins that create holes in the cell membrane allowing the virus to escape and spread, according to a release from Princeton. Drugs that disrupt viroporin production have already been developed for other viruses, including HIV and hepatitis C.

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The key to targeting viroporin production is to figure out how the virus is learning to make the destructive proteins. In the case of hepatitis E, the Princeton researchers found that a section of the virus’ RNA called open reading frame 3 (ORF3) contains the instructions it needs to make viroporins. The research was published in the Proceedings of the National Academy of Sciences.

To prove ORF3 is the key to producing an escape route for hepatitis E particles, the scientists worked with researchers at Rutgers New Jersey Medical School on a model using cells from the African clawed frog. By measuring electric currents, they discovered that ORF3 RNA acts as an “ion channel,” disrupting the cells’ physiology to the point where virus particles could slip through and infect other cells.

Hepatitis E produces only mild symptoms in healthy people, but it is dangerous for people with compromised immune systems and women in the late stages of pregnancy, according to WHO. A vaccine has been developed but is only available in China.

The next step for the Princeton-led team is to find points along the ORF3 pathway that might be able to be targeted with drugs.

"We are working on identifying parts of the protein that could possibly prevent the formation of the ion channel or prevent the flux of ions through the channel," said Alexander Ploss, a Princeton assistant professor of molecular biology and the senior author of the study, in the release.

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