Single Mutation Could Make H5N1 Bird Flu More Dangerous to Humans

Avian influenza viruses usually require multiple mutations to adapt and spread among humans, but what happens when just one change significantly increases the risk of becoming a pandemic virus?

A recent study by Scripps Research, published in Science, reveals that a single mutation in the H5N1 "bird flu" virus, which has recently infected dairy cows in the United States, may enhance the virus's ability to bind to human cells. This discovery highlights the importance of monitoring H5N1’s evolution closely.

Currently, there are no documented cases of H5N1 spreading from person to person. Human infections have been linked to direct contact with contaminated environments, infected dairy cows, poultry, or other animals. However, public health experts are concerned that the virus could eventually develop the ability to spread efficiently between humans, potentially sparking a deadly pandemic.

Flu viruses attach to host cells via hemagglutinin, a protein that binds to glycan receptors on cell surfaces. H5N1 and similar avian influenza viruses typically target avian-type glycan receptors containing sialic acid. To infect humans, the virus must adapt to recognize human-type glycan receptors.

“Monitoring changes in receptor specificity (the way a virus recognizes host cells) is crucial because receptor binding is a key step toward transmissibility. That being said, receptor mutations alone do not guarantee that the virus will transmit between humans,” explained Ian Wilson, D.Phil, study co-senior author and Hansen Professor at Scripps Research.

Past instances of avian viruses adapting to humans required multiple mutations, typically at least three. However, researchers found that a single amino acid mutation, Q226L, in the hemagglutinin protein of the H5N1 2.3.4.4b strain (A/Texas/37/2024) significantly increased the virus’s ability to bind to human-type receptors. This strain was isolated from the first human infection with a bovine H5N1 virus in the U.S.

In this study, the hemagglutinin protein was genetically modified to test its receptor-binding capabilities. Researchers introduced mutations resembling those observed in previous avian viruses. They discovered that the Q226L mutation greatly enhanced the hemagglutinin’s binding affinity for glycan receptors found on human cells.

“The findings demonstrate how easily this virus could evolve to recognize human-type receptors. However, our study does not suggest that such evolution has occurred or that the current H5N1 virus with only this mutation would be transmissible between humans,” said Ting-Hui Lin, study first author and postdoctoral associate at Scripps Research.

Further research revealed that while the Q226L mutation allows the virus to bind to human receptors, additional genetic changes—such as mutations in polymerase basic 2 (E627K), which improve replication in human cells—would likely be required for efficient human-to-human transmission.

“Our experiments revealed that the Q226L mutation could significantly increase the virus’ ability to target and attach to human-type receptors. This mutation gives the virus a foothold on human cells that it did not have before, which is why this finding is a red flag for possible adaptation to people,” added James Paulson, study co-senior author and the Cecil H. and Ida M. Green Chair of Chemistry at Scripps Research.

The findings stress the importance of proactive monitoring of H5N1 and related avian flu strains. Researchers emphasize that even a single mutation increasing the virus’s ability to infect human cells should not be ignored.

“Continuing to track genetic changes as they happen will give us an edge in preparing for signs of increased transmissibility. This type of research helps us understand what mutations to watch for and how to respond appropriately,” Wilson concluded.