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Bird flu in US cows: where will it end?

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A Red and White Holstein is led into the judging area during the World Dairy Expo in Madison, Wisconsin.

Dairy cattle seem to survive infection with the H5N1 strain of influenza virus, which has killed millions of wild birds.Credit: Ben Brewer/Reuters

Concerns that pasteurized milk in the United States is teeming with H5N1 avian influenza virus are over. But there’s no sign that the outbreak in cows is over, and scientists are increasingly concerned that cattle will become a permanent reservoir for this adaptable virus — giving it more chances to mutate and jump to humans.

New data show that the virus can hop back and forth between cows and birds, a trait that could allow it to spread across wide geographical regions. Although the virus kills many types of mammal, most infected cows don’t develop severe symptoms or die1, meaning that no one knows whether an animal is infected without testing it. Moreover, a single cow can host several types of flu virus, which could, over time, swap genetic material to generate a strain that can more readily infect humans.

“Eventually the wrong combination of gene segments and mutations inevitably comes along,” says Michael Worobey, an evolutionary biologist at the University of Arizona in Tucson. “Whatever opportunity we may have had to nip it in the bud we lost by a really slow detection.”

Viral expansion

H5N1 isn’t a new virus — various forms of it have been circulating since the 1990s. A particularly deadly variant that was first detected in 1996 has killed millions of birds and has been found in numerous mammalian species, including seals and mink. But until now, cows were not among the virus’s known hosts.

US officials first announced on 25 March that H5N1 had been found in cattle, and cows from 36 herds in 9 states have tested positive as of 7 May. Tests of pasteurized milk have found no living virus. But the virus’s increasing ubiquity has made scientists uneasy.

“Every time it gets a new mammalian host species like cows, there’s more risk of human transmission and reduced human immunity,” says Jessica Leibler, an environmental epidemiologist at Boston University in Massachusetts.

Bovine breakthrough

Genomic data are starting to shed light on the origins of the cattle outbreak. In a 1 May preprint2 posted on bioRxiv, scientists at the US Department of Agriculture analysed more than 200 viral genomes taken from cows and found that the virus jumped from wild birds to cattle in late 2023. That result corroborates findings by Worobey and others in an analysis posted on the discussion forum virological.org on 3 May. (Neither article has yet been peer reviewed.)

Because cows infected with H5N1 generally don’t die of the flu, they are “effective mixing vessels” in which viruses can swap genetic material with other viruses, says Angela Rasmussen, a virologist at the University of Saskatchewan in Saskatoon, Canada. Even worse, the current strain seems to infect several species equally well. “If you have a virus that’s hopscotching back and forth between cows, humans and birds, that virus is going to have selective pressures to grow efficiently in all those species,” she says.

The larger the number of infected animals, Rasmussen says, the more chances the virus has to acquire helpful mutations, such as the ability to grow in the upper respiratory tract, which could make it more transmissible between people.

Dangerous reservoir

From a human perspective, Worobey says, cows might be one of the worst possible animal reservoirs for influenza because of their sheer number and the degree to which humans interact with them. Culling poultry has curbed previous bird flu outbreaks, but Rasmussen says that isn’t a viable option for cattle. The animals are too valuable and, unlike birds, don’t seem to die from the infection.

H5N1 could even become endemic in cows, says Gregory Gray, an infectious-disease epidemiologist at the University of Texas Medical Branch at Galveston. Other strains related to H5N1 are already endemic in chickens and pigs in some parts of the world.

Researchers aren’t sure how the virus is spreading between herds. Wild birds, which congregate around cattle feed and defecate in the cows’ water supply, are one probable source. “Cattle are just one big birdfeeder,” Gray says, adding that birds can spread infections much further than cows can and are much less controllable.

Some evidence has suggested that farm equipment, such as milking machines, could be to blame, but several scientists worry that it could be airborne. “I’m really thinking that’s occurring and we’ve not been able to study it,” Gray says, mainly because farmers have been reluctant to allow inspectors to test their cattle. Some related variants that infect horses have been found to spread through the air for kilometres, which could explain how the current strain has moved between dairy farms.

Until more is known about the virus’s transmission route, Worobey says, it’s hard to determine the best way to contain it. Since late April, the US Department of Agriculture has required that cows are tested before being transported across state lines. That won’t necessarily stop the virus’s spread, but it could at least help researchers to understand where it’s going.

Herd immunity

If the virus is airborne, Gray says, vaccinating cows might be an option. H5N1 vaccines have not yet been used in US cattle. But influenza vaccines have proved effective in pigs and poultry, and researchers are beginning to test them against the H5N1 strain infecting dairy herds.

Data on how well the virus spreads between people are scarce. A study3 published on 3 May in the New England Journal of Medicine confirmed that one dairy worker in Texas had been infected and that the worker experienced mild symptoms. But the people who worked and live with the infected person have not been tested.

Still, US officials have not reported a large number of deaths or severe cases in humans, suggesting that the virus hasn’t become highly transmissible or deadly, Worobey says.

Below the radar

But Gray says that there have been anecdotal reports of many more human cases. Leibler suspects that exposure of farm workers is widespread. “When you see symptomatic patients, that’s the tip of the iceberg,” she says. In the worst-case scenario, she says, the virus would spread undetected in several species for a long time, accumulating mutations that prime it for causing a pandemic in the future. “We have an awareness now from the COVID pandemic of how devastating that could be,” she says.

Leibler hopes that public-health efforts will begin testing workers and their families so that any transmission in humans will quickly be detected. “H5N1 is with us,” she says. “It’s not a virus that’s going to disappear by any means.”

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Bird flu virus has been spreading in US cows for months, RNA reveals

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A Robotic milker, milks Jersey dairy cows in the milking parlor at the Twin Brook Creamery August 6, 2019 in Lynden, Washington, USA.

A cow is milked in Washington State.Credit: USDA Photo/Alamy

A strain of highly pathogenic avian influenza has been silently spreading in US cattle for months, according to preliminary analysis of genomic data. The outbreak is likely to have begun when the virus jumped from an infected bird into a cow, probably around late December or early January. This implies a protracted, undetected spread of the virus — suggesting that more cattle across the United States, and even in neighbouring regions, could have been infected with avian influenza than currently reported.

These conclusions are based on swift and summary analyses by researchers, following a dump of genomic data by the US Department of Agriculture (USDA) into a public repository earlier this week. But to scientists’ dismay, the publicly released data do not include critical information that would shed light on the outbreak’s origins and evolution. Researchers also express concern that the genomic data wasn’t released until almost four weeks after the outbreak was announced.

Speed is especially important for fast-spreading respiratory pathogens that have the potential to spark pandemics, says Tulio de Oliveira, a bioinformatician at Stellenbosch University in South Africa. The cattle outbreak is not expected to allow the virus to gain the ability to spread between people, but researchers say it is important to be vigilant.

“In an outbreak response, the faster you get data, the sooner you can act,” says Martha Nelson, a genomic epidemiologist at the National Center for Biotechnology Information (NCBI) in Bethesda, Maryland. Nelson adds that with every week that goes by, the window for controlling the outbreak narrows. “Whether we’re not too late, to me, that’s kind of the million dollar question.”

Single spillover

Federal officials announced on 25 March that a highly pathogenic bird-flu strain had been detected in dairy cows. The USDA has since confirmed infections with the strain, named H5N1, in 34 dairy herds in nine states. In late March and early April, the USDA posted a handful of viral sequences from cows sampled in Texas and a sequence from a human case, on the widely used repository GISAID.

On 21 April, the USDA posted more sequencing data on the Sequence Read Archive (SRA), a repository maintained by the NCBI. The latest upload included some 10 gigabytes of sequencing information from 239 animals, includings cows, chickens and cats, says Karthik Gangavarapu, a computational biologist at Scripps Research in La Jolla, who processed the raw data.

Analysis of the genomes suggests that the cattle outbreak probably began with a single introduction from wild birds in December or early January. “It’s good news that there’s only been one jump that we can discern so far. But bad news, in many ways that it has been spreading for probably several months already,” says Michael Worobey, an evolutionary biologist at the University of Arizona in Tucson, who has analysed the genomes.

“This virus is clearly transmitting among cows in some way,” says Louise Moncla, an evolutionary virologist at the University of Pennsylvania in Philadelphia, who has studied the genomic data.

Nelson, who is analysing the data, says she was most surprised by the extent of the genetic diversity in the virus infecting cattle, which indicates that the virus has had months to evolve. Among the mutations are changes to a viral-protein section that scientists have linked to possible adaptation to spread in mammals, she says.

The data also show occasional jumps back from infected cows to birds and cats. “This is a multi-host outbreak,” says Nelson.

A single jump, many months ago, is “the most reliable conclusion you can make,” based on the available data, says Eric Bortz, a virologist at the University of Alaska Anchorage. But an important caveat is that it isn’t clear what percentage of infected cows the samples represent, he says.

Fill in the blank

That’s only one of many data gaps. Scientists lack information about each sample’s precise collection date and the state where it was collected. Such gaps are “very abnormal,” Nelson says.

The missing ‘metadata’ make it harder to answer many open questions, such as how the virus is transmitted between cows and herds, and make it tricky to pin down exactly when the virus jumped to cows. These insights could help to control further viral spread, and protect workers on cattle farms “who can least afford to be exposed,” says Worobey.

Worobey, Gangavarapu and their colleagues are now racing to analyse some metadata uncovered through online sleuthing by Florence Débarre, an evolutionary biologist at the French national research agency CNRS in Paris. Gangavarapu says dates and geographic information for 152 of the 239 samples have been extracted from a USDA presentation posted on YouTube on 26 April.

Researchers also want more swabbing of cattle and wild birds to gain more insights into the outbreak’s exact origin and to decipher another puzzle. The genomic data reveal that the viral genome sequenced from the infected person does not include some of the signature mutations observed in the cattle. “That is a mystery to everyone,” says Nelson.

One possibility is that the person was infected by a separate viral lineage, which infected cattle that have not been swabbed. Another less likely scenario, which can’t be ruled out, says Nelson, is that the person was infected directly from a wild bird. “It raises just a whole slew of questions about what black box of samples we are missing.”

Shilo Weir, a public affairs specialist at the USDA, says the agency decided to post the unanalysed sequence data on the SRA to make it public as soon as possible. Weir says the agency will “work as quickly as possible” to publish curated files on GISAID with relevant epidemiological information, and will continue to make raw data available on the SRA on a rolling basis.

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Bird flu outbreak in US cows: why scientists are concerned

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A group of cows stand in a group in a field at farm in Austin, Texas, USA, 02 April 2024.

A dairy worker in Texas has become infected with a strain of avian influenza similar to that infecting dairy cattle in several US states.Credit: Adam Davis/EPA-EFE/Shutterstock

Researchers are closely monitoring the spread of a worrisome strain of avian influenza to cattle — and one person — at farms in six US states.

These infections represent the first widespread outbreak of bird flu in cows. The outbreak is concerning because humans frequently come into contact with cattle on farms, giving the virus ample opportunity to spread to people, says Daniel Goldhill, an evolutionary virologist at the Royal Veterinary College in Hatfield, UK.

Health officials have said that the overall threat to people remains low, for now, but they are watching the situation unfold closely. “There’s always a worry that viruses will surprise us,” Goldhill says. “We don’t know what they’ll do next.”

Scientists are scrambling to assess how well candidate vaccines and antiviral drugs will work against the circulating strain and to update diagnostic kits for identifying infections in people quickly. They are also trying to understand whether the cows were infected by birds or another source, and are on alert for any changes in the situation that could raise the risk for people.

“There are a lot of questions and, so far, not a lot of answers,” says Florian Krammer, a virologist at Icahn School of Medicine at Mount Sinai in New York City.

Where was the virus found previously, and what’s happening now?

In 1996, the influenza strain called H5N1 was first detected in birds in China. It has been spreading ferociously in birds since 2021, killing hundreds of millions of domestic and wild birds around the world. It has also occasionally infected mammals, including seals and bears, which have become “accidental hosts” of what is mostly an avian virus, says Kanta Subbarao, director of the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia.

In the past two weeks, health officials have detected H5N1 in cows from 16 herds across six states — a number that is likely to increase as US surveillance is stepped up. Researchers have previously documented1 sporadic infections of cows with flu viruses closely related to H5N1, but no widespread outbreaks had been detected until now.

The more mammalian species the virus infects, the more opportunities it has to evolve a strain that is dangerous to humans, Goldhill says. One dairy worker in Texas has been infected, but the US Centers for Disease Control and Prevention (CDC) reports that the person is recovering. The worker’s only symptom was eye inflammation, and viral levels in their nose were low, suggesting that they don’t have a respiratory infection, according to the CDC.

The virus infecting the worker is closely related to the strains found in dairy cattle in Texas, with one notable distinction: the worker’s variant has a mutation that is linked to more-efficient spread in mammals. Goldhill says the presence of the mutation in the human sample was not surprising; it has appeared many times, including in foxes2 and cats3 infected with H5N1.

Is the virus spreading between cows, and why does that matter?

A key question for researchers is how the cows are getting infected. The answer will be important for controlling H5N1’s spread to other farms and people. “This is a controllable situation, we just have to understand how this virus is getting around,” says Richard Webby, a virologist at St. Jude Children’s Research Hospital in Memphis, Tennessee.

Of particular interest is whether the virus is passing from infected cows to uninfected ones, because that would suggest the virus has become more adept at transmission in mammals. Given that the virus has been detected at several farms across the United States, epidemiological data make it “pretty clear now we’re seeing cow-to-cow spread”, and that wild birds are not necessarily involved in viral spread in the farms, says Webby. But there aren’t enough viral sequences of animals infected later in the outbreak for genomic data to confirm cow-to-cow spread, he says.

If the virus is spreading between cows, it will be important to work out precisely how, Webby says. Evidence so far suggest that virus levels are highest in the animals’ milk, according to a report in Science. That suggests that H5N1 might not be spreading between cows through the air, a transmission pathway that would be difficult to control and could allow for relatively quick spread, Webby says. If cows are becoming infected by touching contaminated surfaces, such as milking machines, the virus would be transmitted more slowly than if it is airborne.

Gathering evidence to address these questions could help to answer why infections have only recently cropped up in cattle, and only in the United States, despite the virus’s global spread in the past few years. Marion Koopmans, a virologist at Erasmus University Medical Center in Rotterdam, the Netherlands, wonders whether there is something unique about how cattle are kept in the region, for example, or whether the virus has gained new abilities to persist in the environment. Addressing these questions will offer insights into how widespread bird-flu infections could be in cattle globally, she says. It will be important for health officials outside the United States to start looking for evidence of overlooked outbreaks, Krammer says.

What would increase concern among researchers?

Scientists say that, although bird flu is unlikely to spread widely in people, they are closely monitoring samples of H5N1 globally for mutations known to signal that it is becoming better at spreading in mammals. The virus has not spread widely in humans in part because it can’t readily enter the cells that line the nose and mouth. But it would be problematic if the virus developed mutations that would help it to gain entry to these cells, Goldhill says.

Krammer says he would look specifically for changes to the section of the viral genome that encodes a type of enzyme known as a polymerase. A portion of this enzyme is known to be “a hotspot for adaptation to mammals”. Researchers are also looking out for mutations that would make the strain less susceptible to antiviral drugs, says Webby.

The animal that no virologist wants to see a flu outbreak in, is the pig. Pigs host many influenza A viruses, making them a ‘mixing vessel’ in which strains of avian and mammalian viruses can mix and match and become more efficient at transmitting to people, says Krammer.

What do we know about how well existing vaccines and drugs will work against this strain?

The WHO maintains a list of candidate vaccines that provide protection against H5N1 and that could be mass-produced. And some countries, including the United States, maintain a small stockpile of vaccine doses should they need to vaccinate at-risk populations, such as front-line workers.

The CDC has reported that the viral strain isolated from the infected person is closely related to two strains targeted by a candidate vaccine. Webby says that his team has confirmed in laboratory studies that the WHO vaccines can protect against viral samples collected from cows early in the outbreak, and they will continue to test new samples as the outbreak progresses. Specifically, the vaccine includes antibodies produced against a human H5N8 virus isolated in Russia and an avian H5N1 virus isolated in the United States. They can “recognize this cow virus very, very well”, says Webby.

It would be useful to get more information on how much immunity these candidate vaccines produce against the circulating strain, especially because people don’t have pre-existing protection against H5N1 and closely related viruses, says Subbarao.

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