Cows have human flu receptors, study shows, raising stakes on bird flu outbreak in dairy cattle

In early March, Dr. Barb Petersen, a large-animal vet in Texas, began getting calls from the dairy farms she works with in the Panhandle.?Workers there were seeing a lot of cows with mastitis, an infection of the udder.

Their milk was thickened and discolored, and it couldn’t be explained by any of the usual suspects such as bacteria or tissue damage.

Several more dairies called.?One owner told her he thought his farm had “whatever is going around, and half of my pets have died,” indicating that the contagion had moved beyond cattle.

After running a battery of tests and ruling out every cause she could think of, Petersen sent samples from sick and dead animals to the Texas A&M state veterinary lab and to friends and colleagues at Iowa State University.

What they found – loads of the H5N1 influenza virus – has rocked the dairy industry and put public health officials around the world on alert. It also created an urgent scientific to-do list. One of the first questions that needed to be answered was how the virus was infecting cows in the first place.

Researchers in the US and Denmark took on that task. Their findings, published as a preprint study, show that cows have the same receptors for flu viruses as humans and birds. Scientists fear that cows could be mixing bowls – hosts that help the virus learn to better spread between people. Such an event, while rare, experts say, could put us on the path to another pandemic.

Bird flu tries out new hosts

For years, H5N1, or highly pathogenic avian influenza, has been primarily confined to the bird population, but it has recently begun to infect a growing number of mammals, suggesting that the virus might be adapting and moving closer to becoming a human pathogen.

Avian flu viruses have decimated commercial poultry flocks in the US, and because pigs are known to catch bird flu viruses, swine have been closely monitored for signs of infection – but cows weren’t on anyone’s radar as potential hosts.

Since late March, 42 infected herds have been found in nine states, according to the the US Department of Agriculture. Only one person has been found to be infected with H5N1 after contact with infected cows, and the US Centers for Disease Control and Prevention says the current risk to public health is low, although it is working with states to monitor people with animal exposures.

“The finding in cattle has been so different,” said Dr. Lars Larsen, a professor of veterinary clinical microbiology at the University of Copenhagen in Denmark. In mammals, influenza typically infects the lungs. In cats, it can also infect the brain. “Here we see an enormous amount of virus in the mammary and in the milk,” Larsen said.

Larsen said the concentration of H5N1 viruses in the milk of infected cows is 1,000 times higher than typically seen in infected birds.?He said he and his colleagues calculated that even if the milk from a single infected cow were diluted in 1,000 tons of milk, scientists would still be able to pick up traces of the virus in lab tests.

Tests by the US Food and Drug Administration found inert fragments of genetic material from the H5N1 virus in about 1 out of 5 samples of milk purchased on grocery store shelves, raising questions about how the virus had become so widespread. Researchers confirmed in later tests that the pasteurized milk it tested wasn’t infectious and couldn’t make anyone sick.

That hasn’t stopped the outbreak from rattling more than a few nerves. There’s big money riding on the health of cows. Milk and dairy products were the fourth largest agricultural commodity in the US in terms of cash receipts in 2022, according to the USDA’s economic research service. Sales of cattle and calves were the second largest commodity.

How viruses break into cells

Viruses need a way to hack into cells.?For the virus that causes Covid-19, the key is a receptor called ACE2.?For flu viruses, it’s a sugar molecule that sticks up from the surface of cells called a sialic acid.

Different animals carry different forms, or shapes, of sialic acids. Birds have sialic acid receptors that are slightly different shapes from than the ones humans have in their upper respiratory tracts.

If you hold your index finger straight up, that’s kind of what a bird’s sialic acid receptor looks like, says Dr. Andy Pekosz, a molecular microbiologist and immunologist at Johns Hopkins University.?If you bend your finger at the knuckle into an upside-down L, that’s what human sialic acid receptor looks like. Flu viruses tend to prefer to bind to one shape over the other, he said.

Researchers think this may be one reason why H5N1, which originated in birds, hasn’t been shown to spread efficiently between people.

Until recently, nobody knew what kind of sialic acid receptors cows had, because it was believed that they didn’t catch A-strain flu viruses like H5N1.

Larsen and his colleagues in the US and Denmark took tissue samples from the lungs, windpipes, brains and mammary glands of calves and cows and stained them with compounds that they knew would attach to different kinds of sialic acid receptors.?They sliced the stained tissues very thinly and peered at them under a microscope.

What they saw was surprising: The tiny milk-producing sacs of the udder, called alveoli, were brimming with sialic acid receptors, and they had both the kind of receptors associated with birds and those that are more common in people.?Almost every cell they looked at contained both types of receptors, said lead study author Dr. Charlotte Kristensen, a postdoctoral researcher in veterinary pathology at the University of Copenhagen.

That finding has raised concern because one way flu viruses change and evolve is by swapping pieces of their genetic material with other flu viruses.?This process, called reassortment, requires that a cell be infected with two different flu viruses at the same time.

“If you get both viruses in the same cell at the same time, you can essentially get hybrid viruses coming out of it,” said study author Dr. Richard Webby, director of the World Health Organization Collaborating Centre for Studies on the Ecology of Influenza in Animals and Birds.

In order to be infected simultaneously with two flu viruses – a bird flu virus and a human flu virus – a cell would need to have both kinds of sialic acid receptors, which cows do, something that wasn’t known before this study.

“I think this is probably a pretty rare event,” said Webby, who has been studying the H5N1 virus for 25 years.

In order for something like that to happen, a cow infected with the bird flu virus would need to pick up a different flu strain from an infected human.?Currently, human flu infections are low across the country and dropping as flu season winds down, making the possibility of something like this happening even more remote.

Still, it’s not unheard-of.

Pigs also have both human and bird sialic acid receptors in their respiratory tracts, and flu infections in pigs have been known to spark pandemic viruses.?The 2009 pandemic caused by H1N1 influenza, for example, is believed to have started in pigs in Mexico when the virus reassorted to become one that was able to spread quickly between people.

Another way the bird flu virus could change in cows, Webby says, is more gradual – and more common.

Each time a virus copies itself, it makes mistakes.?Sometimes, those mistakes make the virus less potent and hurt its chances of survival, but in other instances, they’re happy accidents – at least for the virus.?If a bird flu virus happened to change in a way that made it able to bind more easily to the human-type sialic acid receptors in cows, it could gain a survival advantage: the ability to infect more cells and more types of animals, like humans.

Viruses can shift and drift

Reassortment would be a big shift in the evolution of the virus, but the gradual passage of the virus through new hosts could also result in a change to the virus’ genome by evolutionary drift.

Either way, it’s not good news, said Dr. Sam Scarpino, a computational biologist and director of AI and life sciences at Northeastern University.

“We now have a piece of data that suggests the risk profile is higher,” said Scarpino, who was not involved in the new study.

He notes that this is early research.?It needs to be confirmed by a different group of researchers, and it was published quickly as a preprint ahead of scrutiny by outside experts.

But he said the findings are also important because no one had really looked to at the susceptibility of cow tissues to influenza A viruses before.

“This is the first that I’m aware of. It doesn’t mean there isn’t another one out there, but a number of us looked at it pretty carefully and didn’t find any,” he said.

Kristensen said the researchers also couldn’t find any prior research on it, which is why they did the study.

“We just felt that, given the situation, that we should go out with these results as fast as possible,” Larsen said.

Other experts said that although there are more dots to connect, the study clearly raises the level of alert.

“I think we now have more than enough information to conclude that what has to happen is, we need to stop transmission in dairy cattle,” Scarpino said. “We need to increase the kinds of protection that are mandated for workers that are in close contact with cows and milk products and significantly increase the funding that’s going into understanding influenza and in cows, because there’s just a huge amount that we don’t know that we need to learn very quickly.”