A single mutation in the H5N1 “bird flu” virus could enhance its ability to attach to human cells, raising concerns about the potential for human-to-human transmission, according to scientists at Scripps Research. The discovery, published Thursday in Science, highlights the importance of monitoring evolutionary changes in the bird flu virus to assess the risk of a pandemic.
Past cases in which avian viruses have adapted to allow infected people to transmit to other people have typically needed at least three different mutations. But for the H5N1 2.3.4.4b strain, which was isolated from the first human infection with a bovine H5N1 virus in the U.S., the investigators found that a single mutation in an amino acid in the hemagglutinin could switch specificity to binding human-type receptors. The researchers noted that for their research the mutation wasn’t introduced into the entire virus, just the hemagglutinin protein in order to study it’s binding properties.
Since 2021, the H5N1 2.3.4.4b strain has become the dominant strain. Its ability to infect a broad range of species increases the likelihood of mutations that could enable it to spread more effectively in humans.
In their work, the Scripps team introduced several mutations that had been observed in receptor specificity changes in previous avian viruses into the H5N1 2.3.4.4b hemagglutinin protein and soon zeroed in on the Q226L mutation.
“Our experiments revealed that the Q226L mutation could significantly increase the virus’ ability to target and attach to human-type receptors,” said James Paulson, PhD co-senior author of the study and the Cecil H. and Ida M. Green chair of chemistry at Scripps Research. “This mutation gives the virus a foothold on human cells that it didn’t have before, which is why this finding is a red flag for possible adaptation to people.”
The researchers noted that this change alone might not be enough to make the virus transmissible between humans, noting that other changes such as mutations in polymerase basic 2—E627K—which improves viral replication in human cells, would likely be required for efficient spread among humans.
Although the binding affinity of the Q226L mutation to human-type receptors remains relatively weak, historical evidence suggests that weak receptor binding does not necessarily preclude transmissibility. For example, the hemagglutinin of the 2009 H1N1 “swine flu” pandemic virus exhibited similarly weak binding to human-type receptors.
While there is no immediate reason to be concerned about human-to-human transmission, the researchers said continued surveillance of H5N1 and related strains is warranted. Monitoring mutations like Q226L could provide an early warning system for emerging threats and additional research can assess how such mutations might affect other viral properties, including replication, stability, and resistance to immune responses.
“Continuing to track genetic changes as they happen will give us an edge in preparing for signs of increased transmissibility,” added so-senior author Ian Wilson, DPhil, a professor of structural biology at Scripps. “This type of research helps us understand what mutations to watch for and how to respond appropriately.”
There have been no documented cases of human-to-human transmission of H5N1, but the virus has caused sporadic infections in people exposed to contaminated environments or infected animals, including poultry, wild birds, and dairy cows.
H5N1 infection in humans can cause severe illness with high mortality rates. If the virus evolves to spread efficiently between people, it could pose a significant public health threat to an immunologically naïve population.
