Avian Flu Diary: Nature: A Single Mutation in Dairy Cow-Associated H5N1 Viruses Increases Receptor Binding Breadth

Flu Virus binding to Receptor Cells – Credit CDC

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Six months ago we looked at a Preprint: A Single Mutation in Dairy Cow-Associated H5N1 Viruses Increases Receptor Binding Breadth which found that the H5N1 virus has - over time - increased its ability to bind to a wider array of α2,3-linked (avian) receptor cells (see chart below), with the recently emerged A/Texas/37/2024 virus binding to 12 of 13 distinct Neu5Ac glycans.

(A) rH5 binding to distinct Neu5Ac glycans. Green checkmarks indicate a 377 positive binding result for the corresponding glycan. Normalized relative fluorescence 378 unit (RFU) values ± standard deviation are indicated below checkmarks. Value above 379 each glycan indicates the glycan number in the array.

So far, H5N1 has shown little or no affinity for mammalian (α2,6-linked) receptor cells. Humans, however, are not completely devoid of the avian-type receptors, particularly deep in the lungs, which may account for the occasional human infection.

We've discussed receptor binding before, but briefly:

α2,3-linked and α2,6-linked receptor cells have stalks of sugar (carbohydrate) molecules on their surface. These carbohydrate molecules - called `glycans' - form a dense sugary coating to all animal cell membranes. The composition of these stalks varies between types of cells and hosts.

When a virus meets a compatible receptor cell, they are able to `dock', allowing the virus to enter the cell.

The ability to bind to human α2-6 receptor cells is considered the single biggest obstacle that an avian flu virus must overcome in order to successfully jump to humans. So far, H5N1 has yet to make that crucial evolutionary leap.

Yesterday the journal Nature published the full study. While a lengthy and technical read, the gist is: a single mutation (T199I) which emerged in North American birds in late 2023, has increased H5N1's ability to bind to a larger range of avian α2,3-linked glycans.

I've posted the Abstract below. Follow the link to read the full study. I'll have a brief postscript after you return.

A single mutation in dairy cow-associated H5N1 viruses increases receptor binding breadth

Marina R. Good, Monica L. Fernández-Quintero, Wei Ji, Alesandra J. Rodriguez, Julianna Han, Andrew B. Ward & Jenna J. Guthmiller
Nature Communications volume 15, Article number: 10768 (2024) Cite this article

Abstract

Clade 2.3.4.4b H5N1 is causing an unprecedented outbreak in dairy cows in the United States. To understand if recent H5N1 viruses are changing their receptor use, we screened recombinant hemagglutinin (HA) from historical and recent 2.3.4.4b H5N1 viruses for binding to distinct glycans bearing terminal sialic acids using a glycan microarray.

We find that H5 from A/Texas/37/2024, an isolate from the dairy cow outbreak, has increased binding breadth to core glycans bearing terminal α2,3 sialic acids, the avian receptor, compared to historical and recent 2.3.4.4b H5N1 viruses.

We do not observe any binding to α2,6 sialic acids, the receptor used by human seasonal influenza viruses. Using molecular dynamics and a cryo-EM structure of A/Texas/37/2024 H5, we show A/Texas/37/2024 H5 is more flexible within the receptor-binding site compared to a 2.3.4.4b H5 from 2022. We identify a single mutation outside of the receptor binding site, T199I, is responsible for increased binding breadth, as it increases receptor binding site flexibility.

Together, these data show recent H5N1 viruses are evolving increased receptor binding breadth which could impact the host range and cell types infected with H5N1.

(Continue . . . )

While the continued lack of binding to human α2-6 receptor cells is certainly welcome news, there are a number of non-human mammalian hosts which have both avian α2-3 and human α2-6 receptor cells, including swine, felines, bovines, canines, ferrets, marine mammals, and a number of peridomestic species.

Whether through mammalian adaptation, or reassortment, these intermediary hosts could provide the virus with a way forward; towards becoming a more `humanized' pathogen.