Is NRF2 activation the key to treating the herpes virus?

Written by Katie Gordon

Researchers have discovered that the transcription factor NRF2 plays a major role in herpes infection and thus is an effective target for restricting viral infection.

The herpes simplex virus (HSV) is a highly contagious viral pathogen that remains present in the body forever after establishing an infection. For most, the infection results in just small, painful blisters but for those with weak immune systems it can cause inflammation of the brain or lungs.

In order to combat this virus, a team of researchers has used RNA sequencing to examine what happens inside cells during the first few hours of a HSV-1 infection. They discovered that the transcription factor NRF2 plays an important role in this.

The study, published recently in Nature Communications, involved using single-cell RNA sequencing to profile around 12,000 human cells at different time points of a HSV-1 infection. A separate data set was produced for each cell, containing information about the activated genes.

“If you’ve got 12,000 cells and 3,000 analyzed genes, then looking at a huge excel spreadsheet isn’t going to be much help,” explained co-lead author Emanuel Wyler (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association: Berlin, Germany).

By examining the progress of HSV-1 infection in cells, the researchers were able to investigate variations in how the virus develops and identify any factors involved in either encouraging or slowing down the infection.

They discovered that a cell’s vulnerability to infection was affected by what phase of the cell-cycle it was in. Furthermore, they also discovered that the transcription factor NRF2 plays a major role in slowing down the progress of HSV-1 infection.

“I visualized changes in the regulation of each gene we investigated in a single cell. This showed us that the activation level of the NRF2 transcription factor can be a marker for temporary resistance to HSV-1 infection,” commented Vedran Franke (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association).

Based on the finding that NRF2 activation slows down HSV-1 infection, the researchers tested the effectiveness of two drugs, Bardoxolone methyl and Sulforaphane, that are known to activate the NRF2 pathway, in preventing an HSV-1 infection from taking place.

They found that when cells were treated with these NRF2 agonists, the virus activated fewer of its own genes and consequentially virus production was impaired. This suggested that NRF2 activation restricts viral infection.

These results suggest a potential opportunity to prevent HSV infection in those with low immune systems. However, the researchers don’t intend to stop there, with plans already in place to use the same method to investigate another type of herpes virus and coronaviruses.

Until this study, there have been very few attempts to investigate viral infections using single-cell RNA sequencing in this much detail. The researchers hope that these positive results will help to promote the great potential of this method.