Unknown mechanism paving the way for new drugs to combat flu and other viral infections

A new discovery has shown how a number of viruses are able to make use of a certain host protein to multiply. The discovery offers potential for developing drugs for acute viral infections such as HIV and influenza. “There is an urgent need to develop new antiviral drugs,” says Professor Leif Andersson, who is heading the research project.

Project Grant 2017

Development of new therapeutic strategies based on the discovery of ZC3H11A

Principal investigator:
Leif Andersson, Professor of Functional Genomics

Institution:
Uppsala University

Grant in SEK:
SEK 18 million over two years, with a possible extension of a further three years.

The roots of the project can be traced back to the late 1980s, and are a good example of how discoveries in basic research can result in unexpected applications much later on. At that time Professor Andersson and his colleagues at the Swedish University of Agricultural Sciences (SLU) were engaged in mapping pig DNA and the genetic differences between wild boar and domestic pigs.

One important finding they made was to identify a specific mutation that gives the domestic pig more muscles, i.e. more meat and less fat. The findings were published in the scientific journal Nature in 2003, and illustrated how the interaction between an unknown protein and the gene coding for a growth factor played a key role in controlling muscle growth in pigs. A few years later the researchers were able to identify a previously unknown protein they called ZBED6. They also found that the ZBED6 gene is enclosed by another gene, like a Russian matryoshka doll. Andersson elaborates:

“That gene is known as ZC3H11A, and codes for a protein whose function is unknown. It is present in all vertebrates, and must therefore be important – otherwise it would have been lost during the course of evolution.”

Inactivating the gene to study the function

In recent years work on ZBED6 has continued. Meanwhile the researchers have been pondering what function the ZC3H11A protein could have. The modern method being used to investigate this issue is the CRISPR/Cas9 gene editing tool, used to remove and inactivate the gene.

“We tried it out on a human cell line, but didn’t see much difference in how the cell grew,” Andersson comments.

The next step tried by the researchers was to stress the cells by infecting them with a virus to see if the outcome would be any different. When a virus infects a cell, it takes over the cell machinery, and tries to exploit the cell as effectively as possible. But when the ZC3H11A gene had been inactivated, something unexpected happened.

“Much to our surprise, we could see a dramatic decline in the production of virus particles. They were not completely eliminated, but they were drastically reduced in number.”

This phenomenon has now been observed in four separate viruses: adenovirus, influenza virus, HIV and herpes simplex. They all seem to be dependent on the protein for effective growth. Simply put, the virus uses the protein to transport virus RNA from the cell nucleus to the cytoplasm, where the virus particles are produced before dispersing to infect other cells.

The explanation is that these viruses have adapted to use this previously unknown mechanism found in our cells.

“A virus has few genes. It is a small bundle of DNA that enters the host cell, and is heavily reliant on proteins present in that cell. You could say that the virus hijacks a mechanism present in the host cell for its own purposes,” Andersson explains.

His research is now continuing with funding from the Knut and Alice Wallenberg Foundation. The idea is to study the mechanism in greater detail.

“The unusual feature of the mechanism is that it is triggered by stress. When the cell is stressed, the protein is upregulated, probably to ensure export and protein production in stressful situations. When we exposed the cells to heat stress, we could also see an increase in the quantity of protein produced.”

Next, the researchers want to study what happens when the gene is inactivated in living animal models. Perhaps it will be possible to influence the course of a viral infection.

“Naturally, it will be of interest if we succeed in disrupting the interaction between the virus and the protein. It would offer new ways of treating acute viral infections.”

Fear of new pandemics

Several influenza pandemics swept the world in the 20th century. The most severe was Spanish flu, which resulted in the deaths of between 50 and 100 million people from 1918 to 1920. There is widespread anxiety about the risk of a new deadly pandemic. And each year there is also ‘normal’ seasonal influenza, with effects of varying severity.

“It takes a long time to develop an effective vaccine, and in the acute phase we are obliged to rely on antiviral drugs. Discovery of the previously unknown protein could lead to development of new, more effective antiviral drugs, although the route is a long and complicated one,” says Andersson.

Some 30 years have passed since Andersson began mapping the pig genome. He finds it fascinating how basic research can ultimately lead to unexpected, but important, discoveries.

“We had no idea that this is where we would end up when we began crossing domestic pigs with wild boar in the late 1980s. In those days we didn’t even have a detailed map of the human genome, and neither ZBED6 nor ZC3H11A were known to science. But even then, we were absolutely sure we would be able to gain a fundamental biological understanding of the human genome, since different species have remarkably similar gene sets.”

Text Nils Johan Tjärnlund
Translation Maxwell Arding
Photo Magnus Bergström