The influenza virus mutates constantly, and work1 published this month on bioRxiv reveals that this viral volatility can affect whether, and how, a host cell responds to infection.
Genetic sequencing over the past decade has revealed that RNA viruses such as influenza don’t churn out billions of identical copies of their own genomes. Instead, the cells that the virus hijacks produce a messy swarm of viral offspring that carry small genetic errors. Those minor variations can add up as the viruses keep replicating. New mutations could affect how well a virus spreads to other people or how well a person’s immune cells respond.
“Depending on whether a virus has a mutation, maybe it activates the immune system, maybe it doesn’t,” says Jesse Bloom, an evolutionary virologist at the Fred Hutchinson Cancer Research Center in Seattle, and senior study author. “You could imagine that the events in the first few infected cells could get amplified during infection and contribute to the outcome of disease.”
Spotting signals
Researchers have only just started studying these critical first steps of influenza’s evolution in the body. In September, a team led by Ryan Langlois, a virologist at the University of Minnesota in Minneapolis, found that influenza viruses showed differences in their ability to infect different types of lung tissue2. They also found that the body’s immune response was tuned to how many viruses each cell produced.
Bloom and his colleagues took this work one step further. The team isolated 150 cells from a culture of lung tissue infected with a laboratory strain of influenza. The researchers then sequenced the full length of the viral RNAs in each cell. They also measured the number of cellular RNAs telling the cell to produce interferon — a chemical that signals the body’s immune system when a pathogen is present.
Bloom and his colleagues found that they could track how a virus’s mutations affected the kinds of genes that it produced, as well as the amount of interferon that an infected cell manufactured.
Viruses that had major mutations, or were missing entire genes, were more likely to trigger the production of interferon in the cells that they infected.
Opening a window
“What Jesse did with the sequencing is really awesome, though we’ll have to wait for peer review to see how good of a resolution you can get with this approach,” says Seema Lakdawala, a flu virologist at the University of Pittsburgh in Pennsylvania.
The researchers couldn’t follow infected cells over time to track the long-term effects of these viral mutations since the sequencing process killed the cell. And they concede that this work doesn’t explain all of the differences in how cells react to an influenza infection. But the study has “opened a window into how each individual cell is handling an infection”, says Langlois.
This study is about viral evolution on a single-cell level, says Lakdawala, and “it’s neat that we can begin to talk about it”.
