Avian Flu Diary: Preprint: Bovine H5N1 Influenza Viruses Have Adapted to More Efficiently Use Receptors Abundant in Cattle

Positively selected mutations in the cattle H5N1 head domain
are reaching fixation as the virus continues to circulate.

#19,110

We've a fascinating, albeit somewhat technical preprint this morning, which identifies two HA mutations (D104G & V147M) that have become `fixed' and dominant in B3.13 H5N1 isolates (see graphic above) in the two years since the first spillover into Texas cattle.

While these mutations (and others) have been previously elucidated (see Emergence of Antigenic Variants in Bovine H5N1 Influenza Viruses), today's paper links these changes to the virus's successful use of a different type of receptor cell (NeuGc); one that is not found in humans or birds, but is present in cattle and some other mammals.

The authors write:

Whilst humans and birds contain only a single type of sialic acid, N-acetylneuraminic acid (NeuAc), that is usable by influenza viruses 8-10, many mammalian species contain a second type of sialic acid, N-glycolylneuraminic acid (NeuGc).

(Snip)

In several other influenza host species, such as pigs 14,15 and horses 16, high expression of CMAH in tissues results in the display of NeuGc on glycans.

Most influenza viruses preferentially bind to sialylated glycans terminating in NeuAc, and, at best poorly use NeuGc-containing glycans as a receptor 17. However, a now extinct equine H7N7 virus showed a strong preference towards NeuGc 17,18.79

While the B3.13 genotype still retains its strong affinity for NeuAc‑type (avian‑like α2,3‑linked sialic acid) receptors, it has found an alternative sialic acid in cattle it can bind to (NeuGc).

Interestingly, these changes have not been observed in the D1.1 genotypes detected in cattle (see USDA APHIS Reports Wisconsin Dairy Herd Infected With Genotype D1.1).

Today's study has an impressive pedigree, featuring such familiar names as Thomas Peacock, Wendy Barclay, and Ian H Brown. I've only reproduced the abstract and a brief excerpt, so follow the link to read it in its entirety.

I'll have a bit more after the break.

Bovine H5N1 influenza viruses have adapted to more efficiently use receptors abundant in cattle
Jack A. Hassard,Jiayun Yang,Bernadeta Dadonaite, Jonathan E. Pekar, Jin Yu, Samuel A. S. Richardson, Rute M. Pinto, Kristel Ramirez Valdez, Philippe Lemey, Jessica L Quantrill, Jinghan Xue, Tereza Masonou, Katie-Marie Case, Jila Ajeian, Maximillian N.J. Woodall, Rebecca A. Ross, Nicolas Hudson, Kan Zhong, Hongzhi Cao, Samuel Jones, Hannah J. Klim, Brian R. Wasik, Desi N Dermawan, Jean-Remy Sadeyen, Dirk Werling,Dylan Yaffy, Joe James, Alessandro Nunez, Paul Digard, Ian H Brown, Daniel H. Goldhill, Pablo R. Murcia,Claire M. Smith, Yan Liu, Jesse D. Bloom, Munir Iqbal,Wendy S. Barclay, Stuart M. Haslam, Thomas P. Peacock
doi: https://doi.org/10.64898/2026.04.02.715584
This article is a preprint and has not been certified by peer review [what does this mean?].

Preview PDF

Abstract

Sustained mammal-to-mammal transmission of high pathogenicity H5N1avian influenza viruses is reshaping the host range of these pathogens. One of the longest-running mammalian transmission chains involves the B3.13 genotype circulating in U.S. dairy cattle which was detected early in 2024. Genomic analysis revealed selection and rapid fixation of haemagglutinin mutations D104G and V147M.

We demonstrate, via glycomic profiling, that bovine tissues, including the mammary gland, are enriched in N- and O-linked glycans capped with N-glycolylneuraminic acid (NeuGc), a sialic acid absent in humans and birds, which instead express only N-acetylneuraminic acid (NeuAc).

Early cattle H5 viruses poorly recognized NeuGc, but D104G and V147M enabled efficient engagement of both NeuAc- and NeuGc-containing receptors.

These mutations enhanced replication in bovine mammary tissue without major attenuation of replication in human lung and primary nasal epithelial cells. NeuGc-driven receptor adaptation therefore promotes viral fitness in cattle while potentially limiting immediate zoonotic risk. Deep mutational scanning further identifies alternative haemagglutinin substitutions that confer NeuGc usage and represent surveillance markers for emerging cattle H5 lineages.

(SNIP)

Together, these findings suggest that host-specific modifications of sialic acids can act as powerful evolutionary filters shaping influenza receptor usage during mammalian emergence. Incorporating this broader glycan diversity into surveillance frameworks may therefore improve our ability to anticipate host shifts and assess zoonotic risk as influenza viruses continue to expand into new mammalian reservoirs.

(Continue . . . )

While the long-term impact all of this is difficult to predict, the glass-half-full interpretation is; the B3.13 lineage is currently adapting more towards bovine than human hosts.

So far, however, these mutations have only widened the ways that cattle can be infected, and haven't substantially reduced binding to NeuAc-containing receptors.

The most remarkable thing is how quickly B3.13 has developed NeuGc compatible mutations and has turned them into a fitness advantage. We are witnessing active and robust viral adaptation in cattle, not just passive spillover from birds.