More states are finding bird flu in cattle. This is what scientists are watching for

The outbreak of bird flu in dairy cattle is still unfolding.

Both North Carolina and South Dakota have detected the virus in dairy herds, bringing the total number of states affected to eight.

The unlikely spread among cattle and one dairy worker has scientists looking through the data to better understand this spillover. They say the risk to humans hinges on whether the virus can evolve in key ways to better infect mammals.

So far, there's some reassuring news: At a recent meeting, scientists from the U.S. Department of Agriculture said the virus is not presenting like a respiratory illness in cattle – meaning the animals don't appear to be shedding large amounts of virus from their nose or mouths.

Instead, federal health officials investigating the outbreak suspect some form of "mechanical transmission" is responsible for spreading the virus within the herd. This may be happening during the process of milking the cows, a theory supported by the fact that high concentrations of virus are being found in the milk.

"I want to emphasize really how unusual this is," says Thijs Kuiken, a professor of comparative pathology at Erasmus Medical Center. "In other mammalian species with influenza viruses, it's primarily a respiratory disease, which doesn't seem to be the case in these cattle."

The samples collected from infected animals and shared publicly do not suggest the virus has undergone radical changes that would be cause for alarm.

But there are certain signs of trouble in the genome of the virus that scientists are looking out for as it finds a way into more mammals.

"We really need to keep on top of this, because I think we are at a bit of a precipice where something interesting or unfortunate could happen," says Michelle Wille, a senior research fellow at the Center for Pathogen Genomics at the University of Melbourne.

What to watch out for: A virus evolving to infect humans

Genetic sequencing of the virus in the​​ Texas dairy worker showed it had undergone a mutation in a gene, PB2, that commonly gets affected when the virus infects mammals.

This is a clue that the virus is evolving to better replicate inside a mammal, but it's not sufficient to make the virus transmit more easily between humans, says Nichola Hill, a disease ecologist at the University of Massachusetts Boston.

"Sometimes we see these early markers of adaptation," she says, "It needs a handful [of markers] coordinated across multiple different gene segments for it to really be this breakthrough and the next pandemic."

And it would need to become better at transmitting through the air, like the seasonal influenza viruses that humans tend to catch. Currently most cases of bird flu in people are linked to direct contact with an infected animal, oftentime when a chicken is being slaughtered, says David Swayne, a poultry veterinarian who used to work for the USDA.

"It takes a very, very high dose," he says, "It's probably not just exposure to infected poultry – it's exposure to processes that aerosolized the virus."

But the fear is that could change as the virus spends more time in mammals:

Specifically, the protein that the virus uses to bind to cells could evolve to lock onto the receptors in the upper respiratory tract of humans. This would allow it to easily gain access and churn out copies of itself.

"That's considered basically a main barrier that prevents this from becoming a virus that could spread efficiently between people," says Darwyn Kobasa, head of high containment respiratory viruses at Canada's National Microbiology Laboratory.

When the virus has spilled into mammals, scientists have not seen a lot of evolution in this function over the last few years, says Anice Lowen, a professor of microbiology and immunology at Emory University.

Lowen says previous research has shown the protein on the virus would not only need to recognize the human receptors in our upper airways but also become more stable, presumably so it doesn't fall apart during transmission through the air.

These two changes – plus mutations in the PB2 gene to support replication – would all need to come together to support efficient spread in mammals, she says. Of course, she adds, "there's potentially other factors that we don't yet understand."

There are still big questions about exactly how bird flu plays out in cattle, since it's only now being followed closely. "There certainly are many mutations that occurred with this jump from wild birds into cattle and we don't necessarily understand what they mean," says Hill.

How mammals may spread it among themselves: Clues from ferrets

With millions of birds infected all over the globe, it's likely that many mammals are being infected through consuming dead birds or being exposed to feces.

Wille says the virus may have been introduced into dairy cattle in a similar way, perhaps infected birds somehow got into their feed.

"It's not that hard to imagine that we have a sort of contaminated feed situation," she says

But this kind of reasoning may not fully explain mass infection events in some mammals, including "unprecedented" die-offs of seals and sea lions in South America and an outbreak on a mink farm in Spain.

It's still not clear what's driving transmission in those instances, maybe animals were spreading it to each other, says Wille.

Experiments done in labs offer some clues. They have shown mammals can pass on this version of H5N1, and even offer some preliminary evidence suggesting limited airborne transmission.

In one recent study, scientists at the Centers for Disease Control and Prevention analyzed how an isolate of the virus taken from a severe human case in Chile spread among ferrets.

They found that variant had a "high capacity to cause fatal disease" among the animals and that it showed enhanced ability to replicate in human cells cultured in the lab, but "did not exhibit productive transmission in respiratory droplets" or via contaminated surfaces when tested in animals.

A separate study by scientists at Canada's National Microbiology Laboratory infected ferrets in the lab with samples of the virus collected from wild animals.

Those experiments found a particular version of the virus, taken from a hawk, could transmit very rapidly from ferret to ferret through direct contact and cause lethal infection in the originally uninfected animals, says Kobasa, senior author of the study which has not yet been published.

They also found evidence the virus had spread through the air between ferrets in different cages, but they didn't see severe illness in the animals who were infected in this way. It's possible there wasn't enough virus being transmitted to "overcome the immune barriers that would prevent infection," he says.

The results are "very preliminary" and what happens under controlled lab conditions isn't necessarily indicative of what can happen in the wild, he says. "We certainly don't see any changes that would suggest that there's any way to support efficient airborne transmission."

While helpful, Lowen says experiments on ferrets need to be interpreted with caution, especially in the context of humans.

She says overall there's still very limited evidence for transmission through the air: "The fact that ferrets transmit pretty consistently in contact exposure is a bit concerning, but these results don't throw up a lot of red flags for me."

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