Researcher Probes How Viruses Hack Cells

Dermody in a shirt and tie in front of a tan backgroundThis story, written by Kristin Bundy, originally appeared in the Winter 2018/19 issue of Pitt Med magazine.

Virologist Terence Dermody likes to describe viral replication in terms of manufacturing.

Think of a cell as a factory. Maybe a factory that makes flat-screen TVs, he suggests. Then along comes a virus, an inert chemical with instructions for completely rewiring the circuitry. 

“It changes the job of the people in the factory,” said Dermody. “So now, instead of making flat-screen TVs, the cells make thousands and thousands of iPhones.” 

cover of the issue, which has zebras in a groupThe problem with this shift in production, Dermody said, is that it uses up all of the cells’ basic building blocks, forcing the factories to shut down. One by one, as these factories close, the whole community — or related tissues, like those of the liver or the heart — shuts down. 

“How can that be?” Dermody asked. “How does that little inert package recognize a factory and get in there? How does it do the rewiring business? How does the assembly process take place?”

These questions drive Dermody’s current research. Trained in virology, Dermody now focuses on teaching and discovery in his roles as chair of pediatrics at Pitt’s School of Medicine and physician in chief and scientific director at UPMC Children’s Hospital of Pittsburgh

His lab team, notably doctoral students Jonathan Knowlton and Paula Zamora, has worked to decode weak links in viral replication. The goal? To uncover potential therapeutic targets that would disrupt the replication cycle and inhibit viral infection.

Last March in Nature Microbiology, Dermody’s team published findings on a late-stage viral replication process that had not been previously elucidated. They showed that a protein complex in the host cell, called the TRiC chaperonin, guides (or chaperones, if you will) the folding process of the virus’s outer shell, which then creates new viral particles that go on to infect other cells. 

In other words, said Dermody, “These are the final steps of the iPhone manufacturing process — the transport of the iPhones to distributors, then the sale of the iPhone, so people have it in their hands.” 

This discovery was born out of an “unbiased” genetic screen that was designed by Knowlton, with assistance from Zamora. They used the screen to identify cellular protein factors that a relatively simple virus called reovirus requires to replicate. The screening is called unbiased because the researchers had no idea what they will find. 

“We just cast a broad net out into the sea of potential host factors,” said Dermody, “and reeled in what was collected, took a look at the candidates, and ranked them in terms of a priority — which ones were most likely involved in a process of interest and which ones we thought were probably false positives.” 

Interestingly, the researchers knew very little about the TRiC chaperonin before viewing the results of this screening. “You could write what we knew about TRiC on your thumbnail,” said Dermody. They called upon Judith Frydman — a biochemist at Stanford who discovered the TRiC chaperonin protein more than 25 years ago — and cell biologist Cristina Risco in Spain to troubleshoot how to find the precise link between TRiC and the viral assembly pathway. “No one had been able to show that before. That was the main contribution of our paper, and why it was published in Nature Microbiology,” said Dermody.

Now Dermody and the team are posing three questions they hope will reveal more of a virus’s instruction manual on hostile factory takeovers. One: Do other viruses require TRiC to fold their outer shell? That is, is this process generalizable across all types of manufacturing? Two: Can they uncover the complete assembly pathway used to produce the reovirus particles? And three: As it turns out, TRiC is an essential protein for the host and cannot be a target for antiviral therapy. So, are there other aspects of the assembly line that could be a disruption point for treatment?