What we know about how cells take out the trash could fight viruses too

Viruses can infect every kind of life form, from humans all the way down to bacteria. They've managed to spread so far and wide because they have a huge bag of tricks for getting inside cells and multiplying. Some viruses can insert genetic material into their hosts, taking over the machinery of its cells to reproduce. Others lay dormant inside a cell for years until some event triggers them to wake up and burst out of the cell to attack others.

One group of viruses, called positive-sense, single-stranded RNA (+RNA) viruses, plays a game of hide and seek to infect a host. Viruses are sometimes classified by the structure of their genetic material-positive-sense, single-stranded RNA viruses have a single strand of RNA that can act like messenger RNA that tells the host cell what proteins make so it can survive. This group accounts for about one-third of all known viruses, including some of the most well-known, disease-causing viruses out there: hepatitis C, West Nile, dengue, Zika and rhinoviruses that cause the common cold.

When a +RNA virus gets inside a cell, it manipulates the membrane of the cell to create a little compartment, called a replication complex. This compartment helps it hide from the immune system so it can replicate and move on to infect other cells.

Seungmin Hwang, PhD, an assistant professor of pathology at the University of Chicago, studies another common +RNA virus, norovirus. Norovirus is a major cause of what we call "stomach flu" or food poisoning, especially in the winter months. In 2012, while working as a postdoc with the mouse version of norovirus, Hwang discovered that the immune system can detect the replication complex where viruses are hiding inside the cell membrane and attack it. At that point, he didn't know exactly how this worked, but when studying other +RNA viruses he saw the same thing: Somehow, the immune system could "see" the virus in its hiding spot and go after it.

In a new paper published this week in the journal Cell Host & Microbe, Hwang and his team unravel a little bit more of the mystery about how the immune system can sniff out these replication complexes. Just like a household or working office, cells regularly produce trash that needs to be thrown out or recycled. They use a process called autophagy to identify broken down components and unused proteins and wrap them up for disposal. Cells use autophagy proteins to wrap the trash in a membrane-like structure-i.e. its own little garbage bag-and mark it with another autophagy protein so the cell knows to dispose of it.

 

In the new study, Hwang and his team found that cells use the same autophagy proteins to flag replication complexes where viruses are hiding so the immune system can target them. It's like marking some trash for regular recycling, and some of it as hazardous materials for special processing. Just how the immune system distinguishes between regular cellular trash and viruses in hiding isn't clear yet, but the researchers found that this same process works in other +RNA viruses too.

 

Learning more about how the immune system identifies certain types of viruses could be a big help to researchers developing anti-viral treatments. What's more intriguing, Hwang says, is that other pathogens that aren't viruses, like the parasite that causes toxoplasmosis and the bacteria that causes tuberculosis, also build compartments inside cells to hide from the immune system. If scientists can figure out how to target +RNA viruses, it may lead to new ways to fight these diseases too.

"We have broad-spectrum antibiotics to kill bacteria, but there's nothing like that for viruses because they know how to survive inside our body," Hwang said. "If what we found holds true for all other viruses, one day we may come up with a solution that would work against all positive RNA viruses and pathogens that hide inside membranous shelters, because that's a common feature."