The reason why the highly pathogenic H5N1 avian influenza virus, which has been spreading mainly across North American livestock farms since last year, is far more lethal than the European virus has been identified. A protein produced by a mutant gene helped the virus penetrate and replicate well in mammals.
Choi Young-gi and a team led by the head of the Korea Virus Research Institute at the Institute for Basic Science (IBS) said on the 27th in the international journal Science Advances that they "analyzed the genes of the H5N1 virus spreading in North America and found two mutant genes fatal to humans."
The H5N1 virus is a variant of the highly pathogenic avian influenza (HPAI) virus that is lethal to poultry such as chickens and turkeys. It was named H5N1 because the hemagglutinin (HA) and neuraminidase (NA) proteins on its surface are types 5 and 1, respectively. HA acts as a key that allows the virus to attach to human respiratory cells, and NA allows it to pierce through and exit the cell after replication.
The H5N1 virus has already caused large-scale infections in U.S. poultry and cattle, inflicting massive damage. But scientists did not clearly know why this virus penetrates mammals well. Avian influenza can, through mutation, spread to humans and lead to severe illness or death.
The team conducted experiments with ferrets. Ferrets have respiratory structures similar to humans and are often used in influenza research. The experiments showed that the North American H5N1 virus (clade 2.3.4.4b) invaded immune cells and attacked the nervous system. At the center were mutations in the genes that produce the PB2 and NP proteins.
PB2 and NP are proteins that normally play important roles in the replication of influenza viruses. However, in the H5N1 virus spreading in North America, genetic mutations changed the 478th amino acid of PB2 and the 450th amino acid of NP to different types.
Amino acids are the basic units that make up proteins, and there are 20 types. Depending on the order in which they bind, proteins with different structures and functions are formed.
The team explained that PB2 and NP, each altered by a single amino acid, enabled the virus to replicate far more efficiently and to operate within cells. When the researchers reverted the viral gene mutations to their original form, systemic infection did not occur in ferrets.
Additional experiments also confirmed that the mutant virus replicates actively in human immune cells and in bovine mammary gland tissue. This shows that North America's H5N1 avian influenza virus could pose a serious threat not only to poultry but also to mammals such as cattle and humans.
The team said, "The two gene mutations identified this time are important indicators that distinguish pathogenicity," and noted, "To block the threat of infectious diseases, including zoonoses, there is an urgent need for strengthened global surveillance and targeted quarantine measures."
References
Science Advances (2025), DOI: https://doi.org/10.1126/sciadv.ady1208