Under certain conditions, a single H5N1 flu virus mutation could lead to spread among people

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A single mutation in the highly pathogenic influenza (HPAI) H5N1 virus currently circulating among US dairy cows could facilitate its attachment to human cells, enabling person-to-person spread, underscoring the need for continuous surveillance, an experimental Scripps Research Institute study suggests.

But the researchers say other genetic mutations would likely be needed for the virus to prefer human cell receptors to avian receptors and enable efficient human transmission. While circulating H5N1 strains have caused mostly mild illness in dozens of people in the United States exposed to sick wild birds, poultry, dairy cows, and other mammals, the virus doesn't circulate among people.

Using the H5N1 strain isolated from the first US human infection with bovine strain 2.3.4.4b (A/Texas/37/2024), the scientists introduced several mutations into the virus's hemagglutinin (HA) gene sequence to compare the binding of the protein with avian versus human-type cell receptors. Influenza viruses attach to cells via HA, which grabs onto sugar receptors and causes infection.

The mutations, which were chosen to mimic natural mutations, were introduced only onto the HA surface protein and didn't involve the creation of or experimentation with a whole, infectious virus, the authors noted.

The findings were published yesterday in Science.

Receptor binding key to transmissibility

One mutation, the Gln²²⁶Leu substitution (Q226L), enabled the protein to more easily attach to receptors typically found on human cells, particularly in the presence of a second mutation, called Asn²²⁴Lys.

There are likely other mutations we don't yet understand that will be important in combination as relates to the emergence of a pandemic strain.

Michael Osterholm, PhD, MPH

"This is an important study and adds to our broader understanding of the complexities of the hemagglutinin and neuraminidase mutations," said Michael Osterholm, PhD, MPH, director of the University of Minnesota's Center for Infectious Disease Research and Policy (CIDRAP), who wasn't involved in the study.

"However, it doesn't necessarily predict that this virus is close to becoming a human-to-human– transmitted virus," he added. "There are likely other mutations we don't yet understand that will be important in combination as relates to the emergence of a pandemic strain."

With a growing number of H5N1 human infections resulting from contact with infected animals, the results highlight the importance of genomic surveillance to monitor for the emergence of H5N1 mutations, the authors said.

"Monitoring changes in receptor specificity (the way a virus recognizes host cells) is crucial because receptor binding is a key step toward transmissibility," says Ian Wilson, DPhil, co-senior author and the Hansen Professor of Structural Biology at Scripps Research, in a Scripps news release. "That being said, receptor mutations alone don’t guarantee that the virus will transmit between humans."

Flu viruses can mutate rapidly

In expert reaction published in the Science Media Centre, Ed Hutchinson, PhD, of the Medical Research Council-University of Glasgow Centre for Virus Research, said the findings are concerning because influenza viruses can mutate and evolve rapidly.

"For example, recent studies of the influenza viruses in a Canadian teenager, who has been severely ill for a prolonged period with H5N1 bird flu, implied that the virus had begun to evolve to 'explore' ways of binding more effectively to the cells in their body during the course of an infection," said Hutchinson, who wasn't involved with the study.

Ian Brown, PhD, OBE, Thomas Peacock, PhD, and Prof Munir Iqbal, MPhil, PhD, influenza researchers with the Pirbright Institute, added, "It must be stressed that the introduced mutations have not been detected to date in the H5 virus as it naturally transmits between cattle and spills over to avian and mammalian hosts ... As the authors acknowledge, the switch in binding preference is one of several barriers the virus must overcome before it can acquire strong affinity to infect humans and spread between [them]."