Sunday, June 23, 2024

Preprint: A Single Mutation in Dairy Cow-Associated H5N1 Viruses Increases Receptor Binding Breadth

Flu Virus binding to Receptor Cells – Credit CDC


Over the past 3 years it has been pretty obvious that the H5N1 clade virus has been dramatically expanding its host range, both in birds and in mammals.  In the summer of 2022, in DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK, the UK reported:

An increasing proportion of birds of prey/raptor (Accipitriformes) and other resident species (Passeriformes, Columbiformes) have become infected as the outbreak has progressed and more recently, many seabirds including gannets, gulls, guillemots and great skua have become infected throughout June 2022. 

We've seen huge die offs of marine mammals around the world (see EID Journal: Mass Mortality of Sea Lions Caused by HPAI A(H5N1) Virus (Peru)), spillovers into domestic cats and dogs, and the deaths of hundreds of peridomestic mammals (like foxes, raccoons, and skunk), and most recently into dairy cattle, goats, and alpacas. 

Human infections, however, remain rare and (mostly) mild, however no one knows how long that will last, as the virus continues to mutate. 

Today we have a preprint from researchers from Colorado and California which finds 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, 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.

Much of today's (24-page) PDF is quite technical (and well above my pay grade), but 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 provided the link, abstract, and a brief excerpt. Those desiring a deeper dive will want to follow the link to read the report in its entirety. I'll have a brief postscript after the break.
A single mutation in dairy cow-associated H5N1 viruses increases receptor binding breadth
Marina R. Good, Wei Ji, Monica L. Fernandez-Quintero, Andrew B. Ward, Jenna J. Guthmiller
This article is a preprint and has not been certified by peer review [what does this mean?].

Preview PDF


Clade 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 H5N1 viruses for binding to distinct glycans bearing terminal sialic acids.
We found that H5 from A/Texas/37/2024, an isolate from the dairy cow outbreak, has increased binding breadth to glycans bearing terminal a2,3glycans  sialic acids, the avian receptor, compared to historical and recent H5N1 viruses. +
We did not observe any binding to a2,6 sialic acids, the receptor used by human seasonal influenza viruses. We identified a single mutation outside of the receptor binding site, T199I, was responsible for increased binding breadth, as it increased 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.
In this study, we investigated if recent H5N1 viruses are evolving their receptor binding specificities. We identified that H5 from the ongoing dairy cow outbreak has increased binding breadth to backbone glycans bearing α2,3 sialic acids relative to other H5N1 viruses, which was linked to a single mutation near, but not within, the receptor binding site (RBS).
I199 emerged in late 2023, before the onset of the ongoing dairy cow outbreak, and is now the dominant amino acid at this residue in North American isolates. Our study indicates a single mutation near the RBS expands the types of backbone gylcans bound by H5, which could imply an increase in cell, tissue and host tropisms.

          (Continue . . . ) 

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.  And the good news here is that H5N1 has yet to make that evolutionary leap.

But the wider its range of susceptible hosts, the more opportunities it may find to bridge that gap. 

While it may be following a circuitous route, H5N1 continues to rapidly expand its host and geographic ranges, and shows no signs of losing momentum.  It also has the distinct advantage of having scores of genotypes, and variants circulating around the globe, all following their own diverse evolutionary paths. 

Whether any of this leads to a `humanized' H5N1 virus is impossible to know.  There may still be some `species barrier' that protects us (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).

But the recent changes in H5N1 continue to demonstrate why we can ill afford to underestimate this unpredictable and highly mutable virus.