Only one mutation can make H5N1 bird flu a threat to humans

California researchers believe the world may be just one genetic intervention away from human-to-human transmission of the H5N1 bird flu virus – a worrisome mutation that some experts say opens the door to widespread human infections and possibly even a pandemic could.

In a study published Thursday in the journal Science, biologists at the Scripps Research Institute found that a single mutation of the hemagglutinin protein – the “H” in H5N1 – a virus that has primarily sickened or killed birds and cows, could convert into a pathogen that targets cells in humans.

The finding comes amid a growing number of H5N1 outbreaks in California dairy cows and a state-ordered recall of raw milk products. Since the virus began infecting the country’s dairy herd in March, infectious disease experts have warned that unprotected contact between dairy workers and infected cows could cause the virus to evolve in a way that threatens humans.

Now Scripps researchers believe the path to such a genetic change could be much shorter than state and national health officials had expected.

“This really surprised us,” said study co-author James Paulson, a biochemist and molecular biologist. This one mutation “meets a requirement for transmission,” he said.

Richard Webby, director of the World Health Organization’s Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds, said the study’s findings contradict prevailing beliefs about the virus – particularly that multiple mutations are required for the virus to pose a threat to people .

“This will probably cause a stir,” said Webby, who is also a researcher in the division of infectious diseases at St. Jude Children’s Research Hospital in Memphis, Tennessee, and was not involved in the Scripps research.

“I think most of us thought it would probably take more than one change,” Webby said.

Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison and the University of Tokyo, called the Scripps teams’ discovery a “significant discovery” and said it was “critical because, given the mutation rate of influenza viruses, there is one in 10,000 particles.” of the bovine H5N1 virus could carry this mutation.”

That means the possible emergence of an H5N1 virus “that can recognize human receptors is closer than we may have thought,” he said.

A few months ago, Paulson and co-author Ian Wilson, a Scripps structural biologist, decided to study the current H5N1 strain and see what it would take for it to cause a human pandemic.

Paulson is an expert in studying where and how different influenza viruses bind to cells as they invade a host. Wilson studies the structure of influenza virus proteins.

The scientists began their research by accessing a global influenza database and locating the genetic sequence for A/Texas/37/2024 – the H5N1 strain of avian influenza found in a dairy worker in Texas.

They then examined the hemagglutinin proteins, or spikes, on the virus’s outer surface, as these allow it to attach to its host’s cell membrane. Animals such as birds and humans have different docking points on their cells – so-called sialic acid receptors. In order for a flu virus to open the door to a cell and begin replication, it needs just the right thorn or key.

Although more than 50 people have been infected with H5N1, many of these cases are dairy workers who likely had milk from infected cows sprayed into their eyes and noses. Researchers believe that repeated exposure like this allowed the virus to enter the cells – more of a brute force break-in than a lock-picking.

Typically, person-to-person transmission of a flu virus occurs “mainly through the air through droplets from sneezing or coughing, which contains very little virus,” Paulson said. “In this context, the virus must be able to recognize human receptors in order to bind to cells in the human respiratory tract in sufficient quantities to cause infection.”

To figure out what it would take for the virus to acquire the proper docking equipment to trigger a human pandemic, Paulson, Wilson and their team examined previous flu outbreaks that had crossed the bird-human divide, including the flu outbreaks of 1918, 1957, 1968 and 2009 – as well as some earlier studies.

They “selected a series of positions” on the hemagglutinin protein to mutate “one at a time” with amino acids that they knew were involved in previous pandemics.

They then tried to bind these modified “H” proteins with receptor analogs from humans and birds.

And lo and behold: When they swapped a glutamine for a leucine at position 226, it no longer bound to the bird receptors, but only to those in humans.

Paulson said it’s particularly interesting because this mutation had already appeared in previous H5N1 strains, including one from 2010 – but “at the time, this single mutation was not enough to change receptor specificity.” So the unexpected thing is, that the virus has changed in subtle ways – it has evolved, if you will – so that this single mutation now actually changes the receptor specificity.”

Although the researchers showed that the virus can become a threat to humans with just one genetic change, that doesn’t mean nature will take that particular path. A variety of factors can influence the development of an organism and they are not easy to predict. Some say this may be why the virus has not yet gained the ability to infect people on a large scale.

“Despite more than 50 human infections with bovine H5N1, we have seen no evidence that this virus is adapting to humans on a large scale,” Kawaoka said. “This suggests that … additional mutations are likely required for the virus to become fully transmissible between humans.”

Paulson acknowledged that “the context of the entire biological picture is extremely important.”

He said the research only focuses on “one trait that is important for the virus to successfully adapt to a new host,” but there are others that may also be important.

For example, H5N1 was previously known to cause severe respiratory illness. Recently, however, it has most often been associated with conjunctivitis and only occasionally with mild upper respiratory disease.

“Why is that? I don’t think anyone knows,” Paulson said.

What is known is that the virus is spreading rapidly through a variety of species around the world – with ample opportunity for mutation and adaptation.

As of Thursday, the Centers for Disease Control and Prevention had confirmed H5N1 infections in 58 people: 35 from working with infected dairy cows, 21 from infected poultry, and in two cases the source is unknown.

Additionally, 707 dairy herds in 15 states were also infected. And in the last 30 days alone, 23 commercial poultry farms in California have been infected with the virus – affecting more than 5.6 million birds.