Dr. Daphne Avgousti studies viruses and how they hijack the fundamental structures of our cells. She focuses on how viral proteins take advantage of our DNA packaging system that allows all six feet of our DNA to fit into a single cell.
The DNA packaging system that we and other organisms have developed, called chromatin, ensures that our DNA fits into the nucleus, a membrane-bound “piece” inside the cell. Histones are a major component of chromatin and facilitate this storage by allowing DNA to wrap around them like thread around a spool. Chromatin also helps cells control which genes are turned on or off: tighter packaging (including more histones) helps keep genes turned off, while looser packaging helps turn them on.
Viruses also use DNA packaging to adapt their genetic material to virus particles. Adenovirus, one of the viruses studied by Avgousti, uses a histone-like protein called protein VII. This viral protein also changes the chromatin structure of the cells it infects. Avgousti showed that the activity of protein VII has broad implications for its host.
She is also studying how the herpes simplex virus, or HSV, takes advantage of our DNA packaging system. In a preprint published on bioRxivhis team recently reported that HSV co-opts an infection-induced change in host chromatin to exit infected cells, the first step to infecting other cells.
We sat down with Avgousti to learn more about his work, how we can use basic biology lessons from viruses to improve other aspects of human health, and how HSV takes advantage of our chromatin. The conversation has been condensed and edited for clarity.
Why study viruses at this basic level?
You can look at it from the cell side and also from the virus side. If we understand how the cell defends itself, it will help us to strengthen this defense to fight viruses.
On the virus side, viruses take over the cell, that’s what they do – and most of the time they win. Depending on the virus, a person’s immune system overcomes the infection systemically [whole-body] level. But in a cell that is infected? Usually these are curtains for this cell.
Understanding how the virus does this means we can do two things. We can put roadblocks in the way to prevent new infections. But we can also use what we learn from the virus to find other tools.
Do you have an example from your own work?
As a postdoctoral fellow, I discovered that protein VII, an adenovirus DNA encapsidation protein, modifies the chromatin structure of the cell and brings proteins into the nucleus and into the chromatin. It sticks them together like glue so they can’t get out of the cell.
One of these proteins is actually an immune signaling protein. By maintaining it in the cell, the adenovirus prevents the immune response at the systemic level. This allows the virus to spread further.
It changed my life. Like “oh, it actually means something on a higher level” – it’s not just important in a cell. What happens in the nucleus and in the chromatin has systemic implications.
This adenovirus protein is an effective means of deactivating the immune response. We could learn that lesson and potentially develop a drug that could help people with chronic inflammation. We are trying to figure out how to reduce this viral protein to a very small sequence to block inflammation.
You look at how viruses interact with our DNA packaging system. Why do we need to know more about this?
On the positive side, the functioning of chromatin is just one fundamental process of how a cell divides. It is not an easy task. We need to understand how DNA opens and closes at very specific stages of cell division.
And at a fundamental level, all the things we study inform that: How does DNA compaction occur and why? DNA viruses also pack their genomes inside a virus particle, and they do this in different ways. Some of them steal histones from the cell. Some of them have their own histones, some of them use completely different molecules.
The negative reason [for understanding chromatin] it’s that when DNA compaction goes wrong, you get cancer. It’s quite simple. There are thousands of mutations in histone or chromatin modifier genes that correlate with cancer. If you understand how these things work, then you can start fixing these errors.
There are many therapies on the market that alter the way chromatin is modified. A lot of them are very blunt instruments, because you have histones on hundreds of thousands of genes. So if you’re targeting one type of chromatin modification, you’ve just affected 100 important genes [to that cancer] and a thousand who do not.
The more we understand how histones work, the more targeted these therapies can become. And viruses are good at pinpointing exactly what needs to change. By following the virus, we learn something about key chromatin mechanisms.