Genetic change increased bird flu severity during US spread, shows study

St. Jude Children's Research Hospital scientists discovered how the current epizootic H5N1 avian influenza virus (bird flu) gained new genes and greater virulence as it spread west. Researchers showed that the avian virus could severely infect the brains of mammalian research models, a notable departure from previous related strains of the virus.

The researchers genetically traced the virus' expansion across the continent and its establishment in wild waterfowl populations to understand what makes it so different. The study was recently published in Nature Communications.

"We haven't seen a virus quite like this one," said corresponding author Richard Webby, Ph.D., St. Jude Department of Infectious Diseases. "In 24 years of tracing this particular H5N1 flu lineage, we haven't seen this ability to cause disease but also be maintained in these wild bird populations."

When the scientists tested the newer avian flu strains for their ability to cause disease in mammals by infecting a ferret model, they found an unexpectedly high amount of pathogenicity.

"Some of these are really nasty viruses," Webby said. "There's a huge amount of the virus in the brain of infected animals. That's the hallmark of what we saw with these flu strains—increased pathogenicity associated with high virus load in the brain. That's not the first time we've seen H5 viruses in the brain, but these are probably some of the most virulent we've looked at over 24 years of following these viruses."

Previous influenza viruses that caused severe disease in North America "burned out" in their main host bird population, and the outbreaks ended quickly. This current strain was detected at high levels in sick chickens but has expanded into other species.

"This is not just a chicken virus now," Webby said. "It's also infecting other avian and mammal species in the U.S. It's a higher exposure risk for humans and other mammals than we've ever had in North America. We've never really been exposed to this level of circulation of these highly pathogenic flu viruses."

A low risk to humans (for now)

While the newer strains of this H5N1 influenza show a greater ability to cause disease in mammals than earlier viruses, the scientists found it to be low-risk to humans. This is because the virus appears well-adapted to transmit between birds rather than between mammals.

"Overall, their risk to humans is still low," Webby said. "But that risk does seem to be changing, and these viruses are doing things that we haven't seen H5s do before. They've come into the continent's wild bird population, they've reassorted, and they've been maintained over time. There are now many different types out there, and they're very nasty."

Even though the risk of spreading infection is low, the research suggests humans should be cautious interacting with wildlife.

"Someone would have to work pretty hard to infect themselves with this virus. But if they do happen to be infected, there's a real chance of getting a severe disease from it," Webby said. "People just need to be careful and remember that some of the wild animals out there potentially harbor these highly pathogenic viruses."

Genetic change supercharges spread and severity

In the past, similar strains of influenza viruses have not caused similarly severe diseases, nor have they become far-flung in wild bird populations. Since the new strains have done so much more damage, the scientists looked for what was different.

The group identified the direct ancestor to the current strains, which spread from Europe to the Americas after gaining a different version of the viral protein, neuraminidase. This new protein increased the virus's ability to transmit between birds. Then it arrived on the East Coast of Canada and traveled to the United States.

As the researchers studied the virus further, they pinpointed which viruses—distinct from previous ones —caused the current outbreaks. They found that after reaching North America, the virus rapidly changed again to become more virulent. It mixed with flu viruses in North American wild birds, swapping several genes.

This reassortment of genes had two effects. One, the virus seemed to become even more adapted to the bird population, infecting many different types of birds. This included atypical hosts, such as buzzards and eagles, which typically do not get the flu. Second, the virus gained its severe disease-causing properties.

"The surprising thing was that just a few reassortment events did change these viruses' ability to cause disease in our models," Webby said. "And those events generated many different genotypes from that mixing. Then those viruses spread and have now become established in the North American wild bird population."

Webby's group and others continue to monitor the ongoing avian flu pandemic globally to assess its continually evolving risk to both humans and birds.