Friday, December 06, 2024

Science: A Single Mutation in Bovine Influenza H5N1 Hemagglutinin Switches Specificity to Human Receptors



#18,466

Despite their increasing spillover into mammalian species - including this year in dairy cattle - avian influenza viruses like H5N1 and H5N6 still bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds. 

Humanized’ flu viruses - like seasonal H3N2 and H1N1 - have a strong affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system.

While other mammalian adaptations are likely required to create a pandemic strain, the ability of avian flu viruses to bind to human α2-6 receptor cells is considered the single biggest obstacle the virus must overcome in order to successfully spread in humans.

Over the years we've seen speculation that the H5N1 virus was anywhere from 1 to 5 mutations away from becoming a pandemic strain (see 2011's New Scientist: Five Easy Mutations). 
In 2012 - virologists Ron Fouchier and Yoshihiro Kawaoka (working independently) - controversially provided a proof of concept (see Science Publishes The Fouchier Ferret Study) of this theory.

The diversity and spread of HPAI H5 viruses around the world today is at a level today that could scarcely have been imagined a dozen years ago. The virus of 2024 is a far cry from the virus of 2011, and its impact on mammalian species has grown considerably over the past 3 years. 

With scores of human infections this year in the United States - many from a bovine B3.13 genotype - the $65 question is how much does it have to change before it infects humans efficiently?

Yesterday the journal Science published a lengthy and quite detailed research article which identifies a single HA amino acid change (Q226L) which switches H5N1 from binding preferentially to avian receptor cells and to human human receptor cells. 

Q226L is no stranger, and has come up many times before, including: 
PLoS Pathogens: Three Mutations Switch H7N9 To Human-type Receptor Specificity 
Transboundary & Emerg. Dis.: Novel Human-Avian Reassortment H9N2 Virus in Guangdong Province, China

Due to its length and technical nature, I've only provided the link and Editor's summary of the research article below.  Those wanting a deeper dive will want to read the paper in its entirety.

For those wanting a less daunting version, I've provided a link and excerpts from a press release from the Scripps Research Center.   I'll have a brief postscript after the break.

A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors

TING-HUI LIN, XUEYONG ZHU , SHENGYANG WANG , DING ZHANG , RYAN MCBRIDE HTTPS://ORCID.ORG/0000-0001-8616-1910, WENLI YU , SIMEON BABARINDE  JAMES C. PAULSON, AND IAN A. WILSON 

SCIENCE 5 Dec 2024

Vol 386, Issue 6726

pp. 1128-1134

DOI: 10.1126/science.adt0180

Editor’s summary

In 2021, a highly pathogenic influenza H5N1 clade 2.3.4.4b virus was detected in North America that is capable of infecting a diversity of avian species, marine mammals, and humans. In 2024, clade 2.3.4.4b virus spread widely in dairy cattle in the US, causing a few mild human cases, but retaining specificity for avian receptors. Historically, this virus has caused up to 30% fatality in humans, so Lin et al. performed a genetic and structural analysis of the mutations necessary to fully switch host receptor recognition. A single glutamic acid to leucine mutation at residue 226 of the virus hemagglutinin was sufficient to enact the change from avian to human specificity. In nature, the occurrence of this single mutation could be an indicator of human pandemic risk. —Caroline Ash

          (Continue . . . )





Scripps Research scientists identify mutation that could facilitate H5N1 “bird flu” virus infection and potential transmission in humans

New findings underscore the importance of ongoing surveillance for H5N1 mutations that pose risks to public health.

December 05, 2024

LA JOLLA, CA—Avian influenza viruses typically require several mutations to adapt and spread among humans, but what happens when just one change can increase the risk of becoming a pandemic virus? A recent study led by scientists at Scripps Research reveals that a single mutation in the H5N1 “bird flu” virus that has recently infected dairy cows in the U.S. could enhance the virus’ ability to attach to human cells, potentially increasing the risk of passing from person to person. The findings—published in Science on December 5, 2024—highlight the need to monitor H5N1’s evolution.

Currently, there are no documented cases of H5N1 transmitting between people: bird flu cases in humans have been linked to close contact with contaminated environments as well as infected birds (including poultry), dairy cows and other animals. However, public health officials are concerned about the potential for the virus to evolve to transmit efficiently between humans, which could lead to a new, potentially deadly pandemic.

The flu virus attaches to its host via a protein called hemagglutinin that binds to glycan receptors on the surfaces of host cells. Glycans are chains of sugar molecules on cell surface proteins that can act as binding sites for some viruses. Avian (bird) influenza viruses like H5N1 primarily infect hosts with sialic acid-containing glycan receptors found in birds (avian-type receptors). While the viruses rarely adapt to humans, if they evolve to recognize sialylated glycan receptors found in people (human-type receptors), they could gain the ability to infect and possibly transmit between humans.

“Monitoring changes in receptor specificity (the way a virus recognizes host cells) is crucial because receptor binding is a key step toward transmissibility,” says Ian Wilson, DPhil, co-senior author and the Hansen Professor of Structural Biology at Scripps Research. “That being said, receptor mutations alone don’t guarantee that the virus will transmit between humans.”

Past cases in which avian viruses adapted to infect and transmit between people required multiple mutations, usually at least three. But for the H5N1 2.3.4.4b strain (A/Texas/37/2024) isolated from the first human infection with a bovine H5N1 virus in the United States, researchers found that just a single amino acid mutation in the hemagglutinin could switch specificity to binding human-type receptors. Here, bovine refers to the species for dairy cows that were the immediate source of the virus for the human infection. Importantly, the mutation wasn’t introduced into the whole virus—only the hemagglutinin protein to study its receptor-binding properties.

For their study, the research team introduced several mutations into the H5N1 2.3.4.4b hemagglutinin protein that had been involved in receptor specificity changes in previous avian viruses. These mutations were selected to mimic genetic changes that could occur naturally. When the team assessed the impact of one of these mutations, Q226L, on the virus’ ability to bind to human-type receptors, they found that that mutation significantly improved how the virus attached to glycan receptors, which represent those found in human cells.

The findings demonstrate how easily this virus could evolve to recognize human-type receptors,” says first author Ting-Hui Lin, a postdoctoral associate at Scripps Research. “However, our study doesn’t suggest that such evolution has occurred or that the current H5N1 virus with only this mutation would be transmissible between humans.”

Instead, the research team focused on understanding how natural mutations, like Q226L, could arise and what their impact might be. To investigate the potential mutations that could enable the H5N1 2.3.4.4b hemagglutinin to attach to human receptors, the team used advanced binding assays in collaboration with the lab of co-senior author James Paulson, PhD, the Cecil H. and Ida M. Green Chair of Chemistry at Scripps Research. These assays, which are tests to mimic how well a virus attaches to a cell, allowed the researchers to precisely track how the altered H5N1 hemagglutinin interacted with human-type receptors.

“Our experiments revealed that the Q226L mutation could significantly increase the virus’ ability to target and attach to human-type receptors,” explains Paulson. “This mutation gives the virus a foothold on human cells that it didn’t have before, which is why this finding is a red flag for possible adaptation to people.”

The shift alone, however, may not be enough to enable human-to-human transmission. Other genetic changes—such as mutations in polymerase basic 2 (E627K) that enhance viral replication and stability in human cells—would likely be necessary for the virus to spread efficiently among people.
Nevertheless, given the rising number of H5N1 human cases stemming from direct contact with infected animals, the findings highlight the need for proactive surveillance of evolution in H5N1 and similar avian flu strains. While there’s no immediate cause for alarm, the researchers stress that even a single mutation that changes how H5N1 binds to human cells shouldn’t be overlooked.

“Continuing to track genetic changes as they happen will give us an edge in preparing for signs of increased transmissibility,” adds Wilson. “This type of research helps us understand what mutations to watch for and how to respond appropriately.”

In addition to Lin, Paulson and Wilson, authors of the study, “A Single Mutation in Bovine Influenza H5N1 Hemagglutinin Switches Specificity to Human Receptors,” include Xueyong Zhu, Shengyang Wang, Ding Zhang, Ryan McBride, Wenli Yu and Simeon Babarinde of Scripps Research.

This work was supported by funding from the National Institutes of Health NIAID Centers of Excellence for Influenza Research and Response contract 75N93021C00015 / PENN CEIRR.

"The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health."

While this study focuses on a single (A/Texas/37/2024) H5N1 isolate, other studies have shown that this Q226L mutation can be crucial in switching binding properties in a variety of avian flu viruses, including H7N9, H9N2, and most recently H10N3. 

Which is why, even though we are currently focused on the bovine B3.13 genotype here in the United States, we can't afford to ignore the scores of other avian flu genotypes and subtypes that are circulating around the globe. 

Nature is not a one-trick pony, and is perfectly capable of surprising us with something out of left field.