Incorporation of host RNA associated with chronic hepatitis E infection

If the virus incorporates genetic segments of the host into its genome, the infection can become chronic.

Why does hepatitis E become chronic in some patients and why does the treatment not work? To find out, an international research team led by scientists from Bochum observed a patient with chronic hepatitis E infection over the course of a year. Repetitive RNA sequencing of the virus showed that the virus incorporated different parts of the host’s messenger RNA into its genome. This resulted in a reproductive advantage, which may have contributed to the infection becoming chronic.

So-called host RNA insertion can predict the transition from an acute infection to a chronic state.”

Dr. Daniel Todt, head of the Computational Virology research group, Department of Medical and Molecular Virology, Ruhr University Bochum, Germany

The researchers report in the journal Nature Communications on June 6, 2024.

Virus population sequencing

About 20 million people worldwide are infected with hepatitis E each year. Normally, the infection heals without sequelae, but it can be life-threatening for pregnant women or people with suppressed immune systems. In some cases, it becomes chronic. There are no specific effective drugs. The broad-spectrum antiviral drug Ribavirin is also used against hepatitis E, but it does not always work.

How can the virus evade the immune system? Why does the infection become chronic and not cured? The researchers wanted to detect and analyzed for the first time all the viral populations of a chronically infected patient over a period of more than a year. They examined more than 180 individual sequences from blood samples in detail.

Replication in cell culture takes advantage of host RNA

“Hepatitis E virus has a so-called hypervariable region in its genetic information, in which it can incorporate different RNA sequences from host cells,” describes Daniel Todt. His team was able to show that the composition of this region changed massively during the observation period. Moreover, many different compositions took place simultaneously. In cell culture experiments, it was shown that incorporating the host’s RNA provides a replication advantage: the altered viruses can replicate better than others. “We hypothesize that this is partly responsible for the infection becoming chronic and the therapy failing,” says Daniel Todt.

The researchers examined the composition of the host RNA incorporated into the virus to determine if there were any common features that characterized the gene segments. “However, we could not detect any significant similarities,” says Todt. The incorporated gene sequences are mainly those that are very common in the host cells, indicating a random selection.

“Perhaps, during hepatitis E infection, a race between the virus and the immune system takes place in the body,” speculates Daniel Todt. If the virus manages to incorporate the host’s RNA before the immune system successfully fights the infection, it can lead to a chronic course. “Hosting RNA in the viral genome, in any case, can serve as a biomarker in the acute phase of an infection, indicating early on that it is likely to become chronic.”

The researchers plan to expand their studies to larger groups of patients.

funding

The work was funded by the Federal Ministry of Education and Research as part of the new research group “VirBio” and by the German Research Foundation. Further funding came from the Federal Ministry of Health, the German Center for Infection Research and the National Institute of Health.