A colourised transmission electron micrograph of H5N1 virus particles grown in a lab. Image / CDC/NIAID via The New York Times
Scientists from the Scripps Research Institute are reporting that it would take just a single mutation in the version of bird flu that has swept through US cattle herds to produce a virus adept at latching on to human cells, a much simpler step than previously imagined.
To date, there have been no documented cases of one human passing the H5N1 strain of avian influenza to another, the Scripps scientists wrote in their paper, which was published today in the journal Science. The mutation they identified would allow the virus to attach to our cells by hitching itself to a protein on their surface, known as the receptor.
William Schaffner, a professor of infectious diseases at Vanderbilt University Medical Center who did not participate in the study, called the research “sobering”, adding, “I had not known it would take just one mutation in the virus for it to attach itself to the receptors on human cells.”
However, he stressed that the H5N1 virus has been active for 20 years and “has multiplied billions upon billions upon billions of times and the spontaneous mutation that the authors describe” has not been found, despite intense surveillance.
The strain of bird flu detected at a North Otago poultry farm over the weekend is not H5N1, but H7N6, which authorities believe chickens contracted from wild waterfowl.
Yoshihiro Kawaoka, a professor of virology at the University of Wisconsin, who was not involved in the latest H5N1 research but has studied bird flu extensively, said that statistically, the mutation probably already exists in H5N1-infected cows and humans, given that 1 in 10,000 infectious particles of the influenza virus is a mutant.
James C. Paulson, one of the paper’s authors, and several other top scientists agreed that it is statistically likely the mutation has occurred in the H5N1 virus but stressed that it has yet to be detected, and other barriers remain before the virus could be transmitted from one person to another. Paulson is a professor in the Department of Molecular Medicine at Scripps.
Since reaching North America in late 2021, H5N1 avian influenza has infected more than 700 cattle herds and sickened 58 people in the United States. Most of the people infected were farmworkers whose jobs put them in frequent contact with cows or poultry. Most cases have been relatively mild, marked by symptoms such as the eye infection conjunctivitis. However, scientists and health officials have expressed concern about an infected teenager who had been hospitalised for more than two weeks in British Columbia as of November 26. (The Office of the Provincial Health Officer and BC Children’s Hospital both declined to say whether the teenager remains hospitalised.)
In past instances when humans have been infected with strains of bird flu, the mortality rate among those hospitalised has reached 30% or higher.
Because very few people have been infected with avian influenza, our immune systems have not adapted as they have to the seasonal flu. Public health officials worry about the possibility of a virulent strain of avian influenza getting loose in humans, one that could infect cells in the nose, throat and bronchial tubes.
Key factors have prevented this nightmare scenario. The virus has not shown the ability to spread from one person to another. Also, the virus that has infected cows and poultry prefers binding to the surface proteins, or receptors, of bird cells and is not well-suited to human cell receptors.
But all that can change if the virus mutates in the wrong way.
Mutations occur spontaneously as the virus goes through cell division, but they can also occur if a virus infects a cell that is already infected by a different virus. If a person who already has seasonal flu is also infected with H5N1 from a cow or bird, the two viruses exchange genetic material, resulting in a new virus.
The Scripps team worked only with a key protein found on the surface of the virus, not the virus as a whole. They engineered specific mutations in the receptor binding protein found on the surface of H5N1 that had spread from a cow to a person.
However, other research delving into changes that would make the virus a greater threat to humans would probably require engineering a version not found in nature, highly controversial work sometimes called gain-of-function experiments.
“What we need to do is to find out what additional mutations are needed for the bovine H5N1 viruses to become airborne transmissible in mammals,” Kawaoka said. “But we cannot perform such experiments.”
Richard J Webby, a virologist at St Jude’s who was not involved in the study, called the findings “a little frightening”. He added, “I think most people probably would have assumed that it would take a couple of changes to make that switch.”
Not only does the virus have to bind to the human virus receptor, he said, “but you’ve also got to lose the ability to bind to the avian virus receptor, and that’s exactly what this one mutation did”.
Eric Stemmy, deputy chief at the respiratory diseases branch of the National Institute of Allergy and Infectious Diseases (NIAID), said the finding by the Scripps team “wasn’t really all that surprising”. The longer an avian virus circulates in mammals, the higher the risk it will develop mutations that better adapt it to mammalian hosts.
But he said receptor binding is just one aspect that would contribute to possible human transmission. Another is the acidity at which the virus’s receptor-binding protein changes shape – an important step that allows the membranes of the viral and host cells to fuse so that genetic material from the virus can enter the human cell.
Stemmy said the research underscores the need for strong surveillance and pandemic preparedness. The US already has a stockpile of vaccine doses that target H5N1. By the end of the first quarter of 2025, there will be up to 10 million doses, “based on a candidate vaccine virus that remains well-matched to the virus circulating in dairy cattle”, according to a spokesperson for the government’s Administration for Strategic Preparedness and Response.
Paulson said there are still important gaps in what is known about the H5N1 virus that has been found in cows, birds and a small number of humans.
“We may be missing some things frankly,” he said. “Why isn’t the virus causing respiratory disease? That is astonishing to me because, in the past, H5N1 virus caused severe illness.”
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