Hassard et al., (2026) | bioRxiv
06 April 2026
Background
Sialic acid is a collective term for a family of sugar molecules characterized by a nine-carbon backbone. In biological systems, these molecules are located at the terminal ends of complex carbohydrate chains, known as glycans, which are attached to proteins or lipids on the cell surface. These glycans function as the cell’s “external address”; positioned at the outermost interface, they are the primary structures encountered by viruses, bacteria, and other cells. Most Influenza A viruses use sialic acid as a primary receptor, serving as the main docking site for host cell entry. The specific and dynamic presentation of sialic acids varies among species and plays a central role in determining host range and viral tropism.
Two principal linkage configurations are recognized: α2,3-linked sialic acid and α2,6-linked sialic acid. These differ in the chemical bond through which the sialic acid is attached to the penultimate sugar in the glycan chain. In addition, two major forms of sialic acid are known: N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc). The distinction between them arises from a minor chemical modification in the sugar structure.
The Study
A recent study elucidates the molecular mechanism that enabled the H5N1 avian influenza virus to undergo rapid adaptation in U.S. dairy cattle. The findings demonstrate that specific mutations allowed the virus to utilize NeuGc-containing receptors that are abundant in bovine tissues. The outbreak of the H5N1 virus, specifically the B3.13 genotype, among cattle herds in the United States, first identified in early 2024, has raised significant concern within the scientific community. This work defines the molecular pathway underlying this host transition, illustrating how the virus overcame the interspecies barrier. Genomic analyses revealed the selection and rapid fixation of mutations that enable efficient engagement with bovine-specific receptors.
The Key to Adaptation
Most influenza viruses use sialic acid molecules as docking sites; however, the specific form of sialic acid varies among hosts. Humans and birds predominantly express NeuAc, whereas many mammals, including cattle, also express NeuGc. Avian influenza viruses typically bind NeuGc poorly, constituting a substantial biological barrier to infection. In contrast, bovine tissues, particularly the mammary gland, are highly enriched in NeuGc-terminated glycans.
Game-Changing Mutations
Adaptation to cattle involved specific mutations in the haemagglutinin (HA) protein, notably D104G and V147M, which broadened receptor specificity. These mutations emerged independently multiple times and became fixed in circulating H5N1 strains in cattle. Their acquisition enabled high-affinity binding to both NeuAc- and NeuGc-containing receptors. This shift toward NeuGc utilization markedly enhanced viral replication in bovine mammary tissue.
Conclusion
The linkage configuration (α2,3 or α2,6) defines the geometric orientation of attachment, whereas the sialic acid form (NeuAc or NeuGc) defines its chemical identity. Efficient replication of H5N1 in bovine tissues required adaptation to a specific combination, NeuGc presented predominantly in an α2,3-linked configuration.
