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Genetic changes to avian influenza viruses have led to spread among many wild species, creating an uncontrollable global outbreak. Researchers studying the evolution of the bird flu virus over the past 18 years have shown how the strain currently circulating worldwide, an extremely deadly form of the H5N1 subtype, has become increasingly infectious to wild birds. The strain emerged in Europe in 2020, and has spread to an unprecedented number of countries. The study, published in Nature on the 18th October 2023 looked at changes to the virus’s genome over time and used data on reported outbreaks to track how it spread. In 2020, the rate of spread among wild birds was three times faster than that in farmed poultry, because of mutations that allowed the virus to adapt to diverse species. “What was once very clearly a poultry pathogen has now become an animal-health issue much more broadly,” says Andy Ramey, a wildlife geneticist at the US Geological Survey Alaska Science Center in Anchorage. “That has implications for wildlife and domestic poultry as well as us humans that rely upon these resources.” Persistent outbreaks H5N1, classified as a highly pathogenic avian influenza (HPAI) virus because of its high death toll in poultry, was first detected in birds in China in 1996. Outbreaks are usually seasonal, synchronizing with bird migration in Northern Hemisphere autumn. But since November 2021, they have become persistent. In 2022, the virus killed millions of birds across five continents and seeded outbreaks among farmed mink and various marine mammals. To study changes in the virus’s behaviour, the authors examined data reported to the Food and Agricultural Organization of the United Nations and the World Organisation for Animal Health between 2005 and 2022, and analysed more than 10,000 viral genomes. Their work reveals that in mid-2020, a new H5N1 strain evolved from an earlier variety, called H5N8, which first emerged in poultry in Egypt between 2016 and 2017 and caused global flare-ups throughout 2020 and 2021 (see ‘Bird flu outbreaks’). The new H5N1 virus mutated through interactions with non-deadly varieties of bird flu, called low-pathogenic avian influenza (LPAI) viruses, that had been circulating among wild birds in Europe since 2019. It developed two subtypes in 2021 and 2022. One spread across the northern coastal regions of central Europe and was eventually carried to North America by birds migrating across the Atlantic Ocean. The other was carried around the Mediterranean Sea and into Africa. Many bird flu outbreaks begin in poultry, but spillover into wild birds has spread the disease into larger areas, creating a global challenge that is difficult to manage, the study found. “Once it’s adapted to wild birds, we have no mechanism to control the virus. And I think that’s the biggest impact that has changed now,” says co-author Vijaykrishna Dhanasekaran, an evolutionary biologist and virologist at the University of Hong Kong. Louise Moncla, an evolutionary virologist at the University of Pennsylvania in Philadelphia, agrees. “Regardless of how much outbreak response you do in poultry, if it’s coming in from wild birds repeatedly, this is going to be really hard to manage.” “This is really something that most of the world at this point has skin in the game,” adds Ramey. Mixing viruses LPAI viruses often circulate freely in poultry and wild birds. Previous infection with these non-deadly strains is thought to encourage population immunity in wild birds. “You can think of it as an imperfect vaccine, that doesn’t stop infection, but it helps mitigate the effects of disease,” says Ramey. But “there’s probably two sides of the coin here”, he adds. HPAI viruses can mutate through interactions with LPAI ones. In both, the genome is split into eight segments that can be mixed and matched. “When two viruses co-infect the same cell, they could swap their genes when the virus is getting packaged,” says Dhanasekaran. Because of this, LPAI viruses — especially a strain called H9N2 — play a major part in the evolution of H5N1, he adds. But they are not well monitored. “Eradication or elimination strategies that target these low pathogenic viruses would be a huge step forward in terms of controlling avian influenza itself,” says Dhanasekaran. Research Cited published in Nature (Oct. 18, 2023): https://doi.org/10.1038/s41586-023-06631-2
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A new study highlights both the promise and the limitations of gene editing, as a highly lethal form of avian influenza continues to spread around the world. Scientists have used the gene-editing technology known as CRISPR to create chickens that have some resistance to avian influenza, according to a new study that was published in the journal Nature Communications on Tuesday. The study suggests that genetic engineering could potentially be one tool for reducing the toll of bird flu, a group of viruses that pose grave dangers to both animals and humans. But the study also highlights the limitations and potential risks of the approach, scientists said. Some breakthrough infections still occurred, especially when gene-edited chickens were exposed to very high doses of the virus, the researchers found. And when the scientists edited just one chicken gene, the virus quickly adapted. The findings suggest that creating flu-resistant chickens will require editing multiple genes and that scientists will need to proceed carefully to avoid driving further evolution of the virus, the study’s authors said. The research is “proof of concept that we can move toward making chickens resistant to the virus,” Wendy Barclay, a virologist at Imperial College London and an author of the study, said at a news briefing. “But we’re not there yet.” Some scientists who were not involved in the research had a different takeaway. “It’s an excellent study,” said Dr. Carol Cardona, an expert on bird flu and avian health at the University of Minnesota. But to Dr. Cardona, the results illustrate how difficult it will be to engineer a chicken that can stay a step ahead of the flu, a virus known for its ability to evolve swiftly. “There’s no such thing as an easy button for influenza,” Dr. Cardona said. “It replicates quickly, and it adapts quickly.” What to Know About Avian Flu The spread of H5N1. A new variant of this strain of the avian flu has spread widely through bird populations in recent years. It has taken an unusually heavy toll on wild birds and repeatedly spilled over into mammals, including minks, foxes and bears. Here’s what to know about the virus: What is avian influenza? Better known as the bird flu, avian influenza is a group of flu viruses that is well adapted to birds. Some strains, like the version of H5N1 that is currently spreading, are frequently fatal to chickens and turkeys. It spreads via nasal secretions, saliva and fecal droppings, which experts say makes it difficult to contain. Should humans be worried about being infected? Although the danger to the public is currently low, people who are in close contact with sick birds can and have been infected. The virus is primarily a threat to birds, but infections in mammals increase the odds that the virus could mutate in ways that make it more of a risk to humans, experts say. How can we stop the spread? The U.S. Department of Agriculture has urged poultry growers to tighten their farms’ biosecurity measures, but experts say the virus is so contagious that there is little choice but to cull infected flocks. The Biden administration has been contemplating a mass vaccination campaign for poultry. Is it safe to eat poultry and eggs? The Agriculture Department has said that properly prepared and cooked poultry and eggs should not pose a risk to consumers. The chance of infected poultry entering the food chain is “extremely low,” according to the agency. Can I expect to pay more for poultry products? Egg prices soared when an outbreak ravaged the United States in 2014 and 2015. The current outbreak of the virus — paired with inflation and other factors — has contributed to an egg supply shortage and record-high prices in some parts of the country. Avian influenza refers to a group of flu viruses that are adapted to spread in birds. Over the last several years, a highly lethal version of a bird flu virus known as H5N1 has spread rapidly around the globe, killing countless farmed and wild birds. It has also repeatedly infected wild mammals and been detected in a small number of people. Although the virus remains adapted to birds, scientists worry that it could acquire mutations that help it spread more easily among humans, potentially setting off a pandemic. Many nations have tried to stamp out the virus by increasing biosecurity on farms, quarantining infected premises and culling infected flocks. But the virus has become so widespread in wild birds that it has proved impossible to contain, and some nations have begun vaccinating poultry, although that endeavor presents some logistic and economic challenges. If scientists could engineer resistance into chickens, farmers would not need to routinely vaccinate new batches of birds. Gene editing “promises a new way to make permanent changes in the disease resistance of an animal,” Mike McGrew, an embryologist at the University of Edinburgh’s Roslin Institute and an author of the new study, said at the briefing. “This can be passed down through all the gene-edited animals, to all the offspring.” CRISPR, the gene-editing technology used in the study, is a molecular toolthat allows scientists to make targeted edits in DNA, changing the genetic code at a precise point in the genome. In the new study, the researchers used this approach to tweak a chicken gene that codes for a protein known as ANP32A, which the flu virus hijacks to copy itself. The tweaks were designed to prevent the virus from binding to the protein — and therefore keep it from replicating inside chickens. The edits did not appear to have negative health consequences for the chickens, the researchers said. “We observed that they were healthy, and that the gene-edited hens also laid eggs normally,” said Dr. Alewo Idoko-Akoh, who conducted the research as a postdoctoral researcher at the University of Edinburgh. The researchers then sprayed a dose of flu virus into the nasal cavities of 10 chickens that had not been genetically edited, to serve as the control. (The researchers used a mild version of the virus different from the one that has been causing major outbreaks in recent years.) All of the control chickens were infected with the virus, which they then transmitted to other control chickens they were housed with. When the researchers administered flu virus directly into the nasal cavities of 10 gene-edited chickens, just one of the birds became infected. It had low levels of the virus and did not pass the virus on to other gene-edited birds. “But having seen that, we felt that it would be the responsible thing to be more rigorous, to stress test this and ask, ‘Are these chickens truly resistant?’” Dr. Barclay said. “‘What if they were to somehow encounter a much, much higher dose?’” When the scientists gave the gene-edited chickens a flu dose that was 1,000 times higher, half of the birds became infected. The researchers found, however, that they generally shed lower levels of the virus than control chickens exposed to the same high dose. The researchers then studied samples of the virus from the gene-edited birds that had been infected. These samples had several notable mutations, which appeared to allow the virus to use the edited ANP32A protein to replicate, they found. Some of these mutations also helped the virus replicate better in human cells, although the researchers noted that those mutations in isolation would not be enough to create a virus that was well adapted to humans. Seeing those mutations is “not ideal,” said Richard Webby, who is a bird flu expert at St. Jude Children’s Research Hospital and was not involved in the research. “But when you get to the weeds of these particular changes, then it doesn’t concern me quite so much.” The mutated flu virus was also able to replicate even in the complete absence of the ANP32A protein by using two other proteins in the same family, the researchers found. When they created chicken cells that lacked all three of these proteins, the virus was not able to replicate. Those chicken cells were also resistant to the highly lethal version of H5N1 that has been spreading around the world the last several years. The researchers are now working to create chickens with edits in all three of the genes for the protein family. The big question, Dr. Webby said, was whether chickens with edits in all three genes would still develop normally and grow as fast as poultry producers needed. But the idea of gene editing chickens had enormous promise, he said. “Absolutely, we’re going to get to a point where we can manipulate the host genome to make them less susceptible to flu,” he said. “That’ll be a win for public health.”
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