In early March, Dr. Barb Petersen, a large animal veterinarian in Texas, began receiving calls from the dairy farms she works with in the Panhandle. Workers there saw many cows with mastitis, an infection in the udder.
Their milk was thick and discolored, and it couldn’t be explained by any of the usual suspects like bacteria or tissue damage.
Several other dairies called. One owner told her he thought his farm had “everything going on and half my pets died,” indicating that the contagion had gone beyond livestock.
After running a battery of tests and ruling out every cause he could think of, Petersen sent samples of sick and dead animals to the Texas A&M state veterinary laboratory and to friends and colleagues at Iowa State University.
What they discovered – a large quantity of H5N1 flu viruses – shook the dairy industry and put public health authorities around the world on alert. He 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.
Researchers in the US and Denmark have taken on this task. Their findings, published as a prepress 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 spread better between people. Such an event, although rare, experts say, could put us on the path to another pandemic.
Bird flu tests new hosts
For years, H5N1, or highly pathogenic avian influenza, was mainly confined to the bird population, but recently it has begun to infect an increasing number of mammals, suggesting that the virus may be adapting and moving closer to becoming a human pathogen.
Bird flu viruses have decimated commercial poultry flocks in the US, and because pigs are known to contract bird flu viruses, pigs have been closely monitored for signs of infection – but cows weren’t on anyone’s radar as potential hosts.
Since the end of March, 42 infected herds have been found in nine states, according to the U.S. Department of Agriculture. Only one person has been infected with H5N1 after contact with infected cows, and the U.S. Centers for Disease Control and Prevention says the current risk to public health is low, although it is working with states to monitor people exposed to animals.
“The discovery in cattle was very different,” said Dr. Lars Larsen, 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 a huge amount of virus in the breast and milk,” Larsen said.
Larsen said the concentration of the H5N1 virus in the milk of infected cows is 1,000 times higher than that normally seen in infected birds. He said he and his colleagues calculated that even if milk from a single infected cow was diluted in 1,000 tons of milk, scientists would still be able to detect traces of the virus in laboratory tests.
Tests by the U.S. Food and Drug Administration found inert fragments of genetic material from the H5N1 virus in about 1 in 5 milk samples purchased on supermarket shelves, raising questions about how the virus became so widespread. The researchers confirmed in subsequent tests that the pasteurized milk they tested was not infectious and could not make anyone sick.
That didn’t stop the outbreak from rattling more than a few nerves. There is a lot of money invested in cow health. Milk and dairy products were the fourth largest agricultural commodity in the US in terms of cash receipts in 2021, according to the USDA Economic Research Service. Cattle and calf sales were the second largest commodity.
How viruses invade cells
Viruses need a way to invade 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 out from the surface of cells called sialic acid.
Different animals carry different forms or formats of sialic acids. Birds have slightly different shaped sialic acid receptors than humans have in their upper respiratory tract.
If you hold your index finger up, this is 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 joint into an inverted L, this is what the human sialic acid receptor looks like. Flu viruses tend to prefer to attach themselves to one form over another, he said.
Researchers think this may be one reason why H5N1, which originated in birds, has not been shown to spread efficiently among people.
Until recently, no one knew what type of sialic acid receptors cows had because it was believed that they did not contract strain A flu viruses such as H5N1.
Larsen and his colleagues in the US and Denmark took tissue samples from the lungs, tracheas, brains and mammary glands of calves and cows and stained them with compounds they knew would bind to different types of sialic acid receptors. They cut the stained tissues into very thin slices and examined them under a microscope.
What they saw was surprising: The udder’s little milk-producing sacs, called alveoli, were packed with sialic acid receptors and had both the types of receptors associated with birds and those that are more common in people. Almost all of the cells analyzed contained both types of receptors, said study lead author Dr. Charlotte Kristensen, a postdoctoral researcher in veterinary pathology at the University of Copenhagen.
This discovery raised concern because one of the ways flu viruses change and evolve is by exchanging pieces of their genetic material with other flu viruses. This process, called reassortment, requires a cell to be infected with two different flu viruses at the same time.
“If you put 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 Center for Studies on the Ecology of Influenza. . in Animals and Birds.
To be infected simultaneously with two flu viruses – an avian flu virus and a human flu virus – a cell would need to have both types of sialic acid receptors, which cows do, something that was not 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.
For something like this to happen, a cow infected with the bird flu virus would need to contract a different strain of flu from an infected human. Currently, human flu infections are low across the country and decline as the flu season ends, making the possibility of something like this happening even more remote.
Still, it’s not unprecedented.
Pigs also have human and bird sialic acid receptors in their respiratory tracts, and flu infections in pigs are known to trigger pandemic viruses. The 2009 pandemic caused by the H1N1 flu, for example, is believed to have started in pigs in Mexico when the virus recomposed itself and became able to spread quickly between people.
Another way the bird flu virus can change in cows, Webby says, is more gradual — and more common.
Every time a virus copies itself, it makes mistakes. Sometimes these mistakes make the virus less potent and harm its chances of survival, but in other cases, they are happy accidents – at least for the virus. If a bird flu virus changed in a way that made it able to bind more easily to 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 change and fluctuate
The rearrangement would be a major change in the evolution of the virus, but the gradual passage of the virus through new hosts could also result in a change in the virus genome through 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 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 was published quickly as a preprint before scrutiny from outside experts.
But he said the findings are also important because no one had really looked at the susceptibility of cow tissues to influenza A viruses before.
“This is the first one I know of. That doesn’t mean there aren’t others out there, but some of us looked very carefully and didn’t find any,” he said.
Kristensen said the researchers also couldn’t find any previous research on the topic, which is why they did the study.
“We felt that given the situation we should release these results as quickly 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 needs to happen is we need to interrupt transmission in dairy cattle,” Scarpino said. “We need to increase the types of protections required for workers who are in close contact with cows and dairy products and significantly increase funding going toward understanding flu and cows, because there is a huge amount we don’t know that we need to learn very quickly.”
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