Imagine that your friend makes excellent lasagna, and you decide you want lasagna for dinner. Somehow, you want to get yourself invited into his kitchen.
You may start by walking up to his front door and ringing the doorbell. The doorbell signals to your friend that you want to come inside, and maybe even sparks a chain reaction that results in your friend inviting you into his kitchen. Then you can reap the benefits of your visit!
This is what many viruses have to do. Viruses can’t make their own lasagna—ok, not actually lasagna, but the machinery they need to replicate—so they need to steal someone else’s. And to get at the goods, they somehow have to signal to cells from the outside to be let in.
Since there’s no cell doorbell, how does the virus signal to the cell that it wants to be let inside? That is the question Samantha Read asked for her dissertation project in the department of Molecular, Cellular, and Developmental Biology. Specifically, she studied how a family of viruses, called polyomaviruses, bind and signal to cells in order to get inside and start replicating.
Polyomaviruses infect many different animals, including humans, and are incredibly common. Some human polyomaviruses are present in up to 80 percent of people, usually without causing symptoms. But when they do cause symptoms, such as when they infect people whose immune systems are not working well, they can be very destructive. For example, one kind of polyomavirus called John Cunningham virus can cause a progressive type of brain damage when patients have weakened immune systems.
To study how this family of viruses enter cells, Read used the mouse polyomavirus, or murine polyomavirus. She knew that murine polyomavirus binds to certain molecules on the surfaces of cells: molecules made up of fat and sugars, called gangliosides, as well as a protein called α4-integrin. But she suspected that just binding these molecules wasn’t enough to let the virus inside. In a recent publication, Read showed that when murine polyomavirus binds these molecules (rings the doorbell), there’s a chain reaction inside the cell, and certain signaling pathways are switched on. These signaling pathways, called the PI3K and FAK/SRC pathways, have to be turned on if the virus wants to get inside to get its lasagna.
Although Read found that these pathways are important for viral reproduction, it wasn’t immediately clear when during infection the virus needs these signals to be turned on. She wanted to know whether the virus needed them to get inside cells, to move around cells, or to start reproducing themselves. When she showed that these signaling pathways are important for entry, instead of being important once the virus is already inside the cell, it was this result that most excited her.
“The day I saw that PI3K inhibition blocked infection during virus entry but not post entry was pretty awesome,” said Read. “I probably got out cells to repeat the experiment ASAP!”
She thinks that this may apply to other polyomaviruses, not just the mouse version.
“I think some aspects may be conserved,” she said. “Gangliosides are ubiquitous and all polyomaviruses use ganglioside receptors for infection.”
The paper proposes that because these pathways are so important for viruses to get inside a host’s cell, they could be targets for drugs that would prevent viral infection, especially when patients don’t have a fully functioning immune system. Hopefully Read’s work will help to prevent these patients from getting even sicker.
Read will be keeping an eye on how her work is applied, although she has since graduated with her PhD in Molecular, Cellular and Developmental Biology. She says it was tough to leave her dissertation project behind. “The hardest part of this project was putting down the pipet and letting go of the experiments I didn't get to do!” she said. “You always want to do more and there is a point where you have to decide that there is enough of a story to write it up and focus on publishing.”
Her focus paid off, as Read published this work in the journal mBio in 2016 and is currently working as an Immunology Scientist at Merck.
By Alison Gilchrist