Concern surrounding the highly pathogenic avian influenza H5N1 influenza virus currently circulating in dairy cows in the United States is growing. A total of 58 human cases have been reported as of December 9. The vast majority of those cases were known to have been transmitted from either cattle (35) or poultry (21), with two having an unknown source. There is no evidence of person-to-person transmission in the United States, but this is what epidemiologists are watching closely. Once the virus is able to move directly from human to human, the course of the outbreak is likely to change.
Now, new work from a group from the Scripps Research Institute in La Jolla suggests that a single modification in the Hemagglutinin protein (found on the surface of the virus) could allow for easier transmission among humans.
This work is published in Science in the paper, “A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors.”
Influenza viruses attach to cells using hemagglutinin (HA). The HA binds to glycan molecule (sialic acid) receptors on cells to cause infection. The researchers used the H5N1 strain isolated from the first U.S. human infection with the bovine strain 2.3.4.4b (A/Texas/37/2024) to test how mutations in the HA gene sequence affected the binding of that protein with avian versus human-type cell receptors.
The clade 2.3.4.4b virus was detected in North America in 2021, and was found capable of infecting a diversity of avian species, marine mammals, and humans. It is this clade that has spread widely in dairy cattle in the United States this year. Historically, this virus has caused up to 30% fatality in humans.
The researchers sought to understand the mutations necessary to fully switch host receptor recognition to humans. They found that a single glutamine to leucine mutation at residue 226 of the virus hemagglutinin was sufficient to enact the change from avian to human specificity.
More specifically, “a Gln226Leu substitution switched Texas HA binding specificity to human-type receptors, which was enhanced when combined with an Asn224Lys mutation. Crystal structures of the Texas HA with avian receptor analog LSTa and its Gln226Leu mutant with human receptor analog LSTc elucidated the structural basis for this preferential receptor recognition.”
The researchers introduced several mutations into the viral HA protein that had been observed to occur naturally in the past and found that one mutation, called Q226L, improved the ability of the protein to attach to receptors typically found on human cells, especially when an additional mutation was present. The researchers introduced the genetic mutations only into the HA surface protein and did not create or conduct experiments with a whole, infectious virus.
The experimental finding with the Q226L mutation alone does not mean HPAI H5N1 is on the verge of causing a widespread pandemic, the authors noted. In the setting of a growing number of H5N1 human cases resulting from direct contact with infected animals, the findings stress the importance of continued efforts at outbreak control and continued genomic surveillance to monitor for the emergence of HPAI H5N1 genetic changes and maintain public health preparedness.
The study results reinforce the need for continued, vigilant surveillance and monitoring of HPAI H5N1 for potential genetic changes that could make the virus more transmissible in humans.