US scientists believe the H5N1 flu virus currently circulating in birds and dairy cows is already better at infecting people than earlier variants, and that a single mutation would allow it to bind to key human receptors.
Alarmingly, a single mutation could allow it to infect the cells lining our noses and throats, making it more likely to go airborne, reports New Scientist.
While this change alone is not enough for the virus to be capable of causing a pandemic, if a virus with this mutation swopped genes with a human flu virus, it could acquire pandemic potential almost instantly.
“The more people get infected, the more likely it is that something like this could arise,” said Ian Wilson at the Scripps Research Institute in California. Despite this, Wilson thinks the risk remains low.
A particularly virulent form of H5N1 bird flu evolved in the 1990s, probably in domestic birds in China, and spread worldwide. Around 2020, a new variant of this virus emerged and spread even more widely, reaching the Americas and Antarctica.
It has infected domestic poultry in large numbers and is also spreading among dairy cows in the US, causing occasional human cases.
A team led by Debby van Riel at the Erasmus University Medical Centre in The Netherlands has now infected human nose and throat cells with H5N1 variants from 2005 and 2022. They have shown for the first time that the 2022 variant is better at binding to these cells and also better at replicating inside them. “It’s bad news,” said Van Riel.
“I don’t think the chances of the virus becoming pandemic are extremely high,” she said. But the fact that the virus is better at infecting humans will give it more opportunities to acquire additional mutations that increase its pandemic potential.
Meanwhile, Wilson and his colleagues have been studying the crucial haemagglutinin protein of the flu virus. This protein binds to receptors on the outside of cells, determining which cells the virus can infect. Because it protrudes from the virus, it is also the main target of the immune system, they wrote in Science, where their findings were published.
At present, the H5N1 haemagglutinin binds mainly to receptors that in humans are found deep in the lungs. This means it can cause severe disease but it is unlikely to get out of the body and infect others. To do that, the virus needs to infect cells lining the nose and throat, meaning viruses can be coughed or sneezed out to infect others.
Van Riel’s study, posted on bioRXiv, suggests the virus can do this to some degree, but it’s not clear whether the virus is binding to the main receptors on these cells. It was thought that multiple mutations would be required for H5N1 to bind strongly to these receptors, but Wilson’s team has now shown that with the current H5N1 variant, a single mutation is all it would take.
This change alone would not result in a virus capable of going pandemic, said team member Jim Paulson, also at the Scripps Research Institute. “We view this property as required – but importantly not sufficient – for transmission, for a pandemic virus,” he said.
Other changes are also necessary for the virus to start to replicate and spread from person to person, adds Paulson, and these are not well understood. “There’s a lot of biology that we don’t even know.”
Once an H5N1 virus infecting a human acquired the receptor-switching mutation, however, it would then have a chance of evolving these other changes as well.
What’s more, in theory, it could acquire all of the abilities it needs in one fell swoop by swopping genes with a human virus infecting the same individual. Several previous flu pandemics were caused by animal and human flu viruses swopping genes, said Paulson.
“This is highly concerning,” said Aris Katzourakis at the University of Oxford, who was not involved in either study. “Each spillover to a human gives the virus a roll of the dice.”
How deadly would an H5N1 pandemic be?
If H5N1 bird flu does manage to start spreading from person to person, the big question is how deadly it would be. Of the people confirmed to be infected with the virus since 2003, half have died. However, the true infection fatality rate could be lower as many cases have probably gone undetected, and milder ones are more likely to be missed.
Among the 60 or so people infected in the US since the dairy outbreak began, almost all have had mild symptoms only. Why is not understood, but one explanation is that many were infected via the eyes. “That is known to have far milder outcomes,” said Katzourakis.
It is also thought that when viruses switch from binding to receptors deep in the lungs to those higher in the respiratory tract, they become less dangerous.
But the puzzling aspects of the cases in the US have left Paulson unsure that this will hold true with H5N1. “I just don’t know what to think, to be honest,” he said.
“I don’t think there is any reason to be complacent in this respect, and anticipate ‘mildness’ should this virus become readily human-to-human transmissible,” said Katzourakis.
Wilson’s team studied the haemagglutinin protein in isolation, so there was no chance of a lab leak of the mutant protein. “There was no virus used at all here,” he said.
Study 1 details
A single mutation in bovine influenza H5N1 haemagglutinin switches specificity to human receptors
Ting-Hui Lin, Xueyong Zhu, Shengyang Wang Ding Zhang and Ian A. Wilson
Published in Science on 5 December 5 December 2024
Abstract
In 2024, several human infections with highly pathogenic clade 2.3.4.4b bovine influenza H5N1 viruses in the United States raised concerns about their capability for bovine-to-human or even human-to-human transmission. In this study, analysis of the haemagglutinin (HA) from the first-reported human-infecting bovine H5N1 virus (A/Texas/37/2024, Texas) revealed avian-type receptor binding preference. Notably, a Gln226Leu substitution switched Texas HA binding specificity to human-type receptors, which was enhanced when combined with an Asn224Lys mutation. Crystal structures of the Texas HA with avian receptor analog LSTa and its Gln226Leu mutant with human receptor analogue LSTc elucidated the structural basis for this preferential receptor recognition. These findings highlight the need for continuous surveillance of emerging mutations in avian and bovine clade 2.3.4.4b H5N1 viruses.
Study 2 details
A 2022 avian H5N1 influenza A virus from clade 2.3.4.4b attaches to and replicates better in human respiratory epithelium than a 2005 H5N1 virus from clade 2.3.2.1
Lisa Bauer, Lonneke Leijten, Debby van Riel et al.
Preprint on bioRXiv on 27 November 2024
Abstract
Background
Highly pathogenic avian influenza (HPAI) H5 viruses of the A/Goose/Guangdong/1/1996 (GsGd) lineage pose significant global risks to wildlife, domestic animals, and humans. Recent cross-species transmission events to mammals, including humans, highlight this risk. Critical determinants for cross-species and intra-species transmission include the ability to attach to and replicate in respiratory epithelial cells. Although these factors have been studied for HPAI H5N1 viruses in the past, limited studies are available for currently circulating strains.
Methods
We compared level of adaptation to human respiratory tract of a HPAI H5N1 clade 2.3.4.4b (H5N12022) virus with those of well characterized HPAI H5N1 clade 2.1.3.2 (H5N12005) and seasonal H3N22003 viruses by three methods. First, we compared pattern of virus attachment by virus histochemistry. Second, we compared efficiency of infection and replication, as well as innate immune responses in human respiratory epithelium in vitro. Lastly, we compared polymerase complex activity in a minigenome assay.
Findings
The H5N12022 virus attached more abundantly to and replicated more efficiently in cells of the human respiratory tract compared to H5N12005 and H3N2 viruses. This increased replication was not associated with an increased polymerase activity of H5N12022 virus compared to H3N22003 virus. The efficient replication of H5N12022 virus infection induced a robust innate immune response almost comparable to H3N22003.
Interpretation
The pattern of virus attachment and replication efficiency of a HPAI H5N12022 virus resembled that of H3N22003 virus more closely than a HPAI H5N12005. This could contribute to an increased risk for both human infection and virus adaptations to humans.
See more from MedicalBrief archives:
Teen critical in Canada’s first human bird flu case
Bird flu case raises first suggestion of human transmission