Deadly flu pandemics can arise when influenza viruses circulating in animals acquire the ability to jump to humans. In work published today in the open-access journal eLife, scientists at Fred Hutchinson Cancer Research Center comprehensively mapped the alterations in a key influenza protein that allow bird flu to grow better in people.
The map could help scientists better understand which changes enable flu to jump species and may presage a new pandemic, said flu researcher Dr. Shirleen Soh, a postdoctoral fellow working in the lab of Hutch computational biologist Dr. Jesse Bloom. This understanding, in turn, would be a step toward heading off pandemics by pinpointing which viruses should be targeted with a vaccine.
Though scientists can collect and sequence viruses circulating in the world, “we have no idea how that information translates into how well a particular virus is going to do in a human host,” Soh said. Comprehensive maps of mutations that enable bird flu to grow well in human cells “are one way to build a better model for understanding which viruses might do well [in people] or not.”
Wild waterfowl and swine can harbor strains of the fast-mutating influenza A that are distinct from the strains that cause cases of seasonal flu. When a strain jumps from animals to humans, it can be particularly dangerous. Perhaps the best-known example of this is the 1918 flu pandemic, which killed between 50 and 100 million people around the world.
Previous studies looking at past pandemics had showed that flu doesn’t always jump hosts via the same route. For example, one mutation thought to be critical to human adaptation wasn’t seen during the 2009 swine flu pandemic — instead, two new mutations gave that virus the same ability to replicate in human cells.
Rather than waiting untold years for the virus to naturally find every possible evolutionary path to a new pandemic, Soh and Bloom decided to take matters into their own hands.
They focused their attention on a bird flu protein called PB2, part of the molecular complex the virus uses to copy its genome. Soh mutated the PB2 gene to make every possible change to every building block of the PB2 protein. Then she tested whether each change helped bird flu grow better in human cells.
Importantly, Soh used viruses that can’t infect humans. The genes for PB2 and other proteins that copy the viral genome came from bird flu, but the rest came from a lab-adapted flu strain that can infect human cells in lab dishes — but not actual humans. This allowed Soh to study the effects of PB2 mutations in a safe context.
Soh came up with a list of changes to PB2 that helped bird flu make the switch to human cells. Some had previously been observed in natural cross-species jumps, but some were entirely new. Of the top 34 human-adaptive mutations Soh described, only one had already been shown to help bird flu adapt to humans.
Soh was also able to see that the changes that best enabled viral species-jumping clustered on the surface of PB2, suggesting that they improved its ability to interact with molecules inside human cells. Scientists do not yet know all the factors to which flu must adapt in its new human host.
As new flu strains arise, evolve and spread into humans, scientists collect samples and sequence their genes as part of a global surveillance program. Working with Hutch colleague Dr. Louise Moncla, a postdoctoral fellow in Dr. Trevor Bedford’s lab, Soh and Bloom compared Soh’s list of mutations with those seen in variants of a bird flu strain, H7N9, which first made the leap into people in China in 2013.
“We were able to take Shirleen’s map and see that many H7N9s that jumped into humans did have evidence of adaptive mutations, including some mutations that we hadn’t known about before Shirleen’s mapping experiment,” said Bloom.
These results suggest that the information in their map could help scientists distinguish the mutations that enable the virus to move between species from those that don’t. In the future, this and similar mutation maps might be able to help public health officials identify virus strains likely to cause a pandemic, and perhaps give them extra time to develop a tailored vaccine.
Soh hopes to make their data more accessible to others by working with Moncla and Bedford to incorporate it into their NextStrain platform, which tracks flu evolution in real time. Then anyone interested in a specific mutation will be able to query whether that mutation might help the viruses grow better in people.
“As in any kind of surveillance, it’s not just about collecting the information, it’s about figuring out what it means,” Bloom said, though he cautions that predicting with certainty which viruses will do well in humans is a tall order. “I think this certainly provides a much more informed way of trying to assess what [the flu mutations seen in natural infections] might mean.”
Sabrina Richards, a senior editor and writer at Fred Hutch Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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