In early March, Dr. Barb Petersen, a Texas-based veterinarian specializing in large animals, started receiving inquiries from dairy farms in the Panhandle region. Farmworkers reported a surge in cases of mastitis, a udder infection among cows.
The milk appeared denser and discolored, defying conventional explanations like bacterial infection or tissue damage.
More dairy operations reached out for assistance. One farm owner described his herd as affected by "whatever is going around," noting significant pet losses, suggesting the contagion's spread beyond cattle.
Following exhaustive tests ruling out known causes, Petersen dispatched samples from afflicted and deceased animals to the Texas A&M state veterinary lab and colleagues at Iowa State University.
Their discovery - a substantial presence of the H5N1 influenza virus - has rattled the dairy sector and alerted global public health authorities, prompting an immediate scientific agenda. Among the top priorities was unraveling the mystery of how the virus infiltrated cows.
Researchers in the United States and Denmark embarked on this mission. Their findings, documented in a preprint study, reveal that cows share identical flu virus receptors with humans and birds. Scientists worry that cows might serve as incubators - fostering conditions conducive for the virus to evolve and enhance human-to-human transmission. Although such occurrences are rare, experts caution they could pave the way for another pandemic.
Bird flu tries out new hosts
For years, H5N1, commonly known as highly pathogenic avian influenza, has predominantly affected avian populations. However, recent instances of transmission to mammals suggest potential adaptation towards becoming a human pathogen.
Avian flu outbreaks have devastated commercial poultry flocks in the United States. While pigs are susceptible to bird flu viruses, cows hadn't been considered likely hosts.
Since late March, the US Department of Agriculture has reported 42 infected herds across nine states. Despite one human infection linked to contact with infected cows, the US Centers for Disease Control and Prevention assesses the current public health risk as low, albeit collaborating with states to monitor individuals with animal exposures.
"The discovery in cattle has been unprecedented," remarked Dr. Lars Larsen, a veterinary clinical microbiology professor at the University of Copenhagen. Unlike in birds, where influenza typically targets the lungs, in cows, the virus is notably concentrated in mammary glands and milk.
Larsen's team found H5N1 virus concentrations in infected cow milk to be 1,000 times higher than in birds. Even if diluted in 1,000 tons of milk, traces of the virus could still be detected in laboratory tests.
The US Food and Drug Administration detected inactive genetic material fragments from the H5N1 virus in roughly 20% of milk samples from grocery stores, prompting inquiries into the virus's widespread dissemination. Subsequent tests confirmed that pasteurized milk was non-infectious and posed no health risks.
Nonetheless, the outbreak has sparked considerable concern. The economic stakes are substantial, given that milk and dairy products ranked as the fourth-largest agricultural commodity by cash receipts in the US in 2022, with cattle and calves sales following as the second-largest commodity.
How viruses break into cells
Viruses require a means to infiltrate cells. In the case of the virus responsible for Covid-19, the pivotal factor is a receptor known as ACE2. However, for flu viruses, it's a sugar molecule protruding from cell surfaces called sialic acid.
Various animals harbor distinct variations or configurations of sialic acids. Avian sialic acid receptors possess slightly different shapes compared to those found in the upper respiratory tracts of humans.
Dr. Andy Pekosz, a molecular microbiologist and immunologist at Johns Hopkins University, analogizes a bird's sialic acid receptor to a straight-up index finger, contrasting it with the human receptor resembling a bent finger at the knuckle forming an upside-down L. He notes that flu viruses tend to exhibit preference for one shape over the other.
Scientists speculate this discrepancy may explain why H5N1, originating in birds, hasn't demonstrated efficient transmission among humans.
Until recently, the sialic acid receptor profile of cows remained unknown, as it was believed they weren't susceptible to A-strain flu viruses like H5N1.
Researchers, including Larsen and colleagues from the US and Denmark, conducted tissue sampling from calves and cows' lungs, windpipes, brains, and mammary glands. They stained these samples with compounds designed to attach to different types of sialic acid receptors, then examined them under a microscope.
Their observations were unexpected: the alveoli, tiny milk-producing sacs in the udder, teemed with sialic acid receptors, encompassing both avian-associated and human-associated receptors. Nearly every cell examined harbored both receptor types, highlighting a novel finding.
This discovery raises concerns because one mechanism through which flu viruses evolve is reassortment, wherein genetic material exchange occurs between different flu viruses within an infected cell.
Dr. Richard Webby, director of the World Health Organization Collaborating Centre for Studies on the Ecology of Influenza in Animals and Birds, explains that for simultaneous infection with two flu viruses—a bird flu virus and a human flu virus—a cell necessitates both types of sialic acid receptors, a feature observed in cows for the first time in this study.
Though deemed a rare event, such co-infection potential underscores the dynamic nature of viral evolution. Webby, with 25 years of H5N1 research, underscores the rarity of this occurrence.
However, Webby notes a more gradual and commonplace avenue for change in the bird flu virus within cows: each viral replication introduces errors, some of which may inadvertently enhance the virus's ability to bind to human-type sialic acid receptors, potentially broadening its host range and infectivity, including humans.
Viruses can shift and drift
Reassortment would mark a significant evolutionary shift for the virus, yet the gradual progression through new hosts could also induce genomic alterations via evolutionary drift.
Dr. Sam Scarpino, a computational biologist and director of AI and life sciences at Northeastern University, voices concerns, stating, "We're now presented with data suggesting an elevated risk profile." He emphasizes that this is preliminary research, necessitating validation by independent researchers, published hastily as a preprint before undergoing external expert scrutiny.
While underscoring the significance of the findings, Scarpino underscores the absence of prior investigations into the susceptibility of cow tissues to influenza A viruses. "To my knowledge, this is the inaugural inquiry. While another study may exist, a thorough examination didn't reveal any," he remarked.
Kristensen, the lead study author, acknowledges the dearth of prior research on the subject, motivating their investigation.
Larsen, echoing Kristensen's sentiment, underscores the urgency of disseminating the results given the circumstances.
Other experts echo the sentiment that while more connections need elucidation, the study notably heightens alertness.
"I believe we now possess ample evidence to assert that halting transmission in dairy cattle is imperative," asserts Scarpino. "We must enhance mandated safeguards for workers in close proximity to cows and dairy products and substantially augment funding for influenza research in cows, as there's a vast expanse of knowledge gaps that necessitate swift comprehension."
