When H5N1 bird flu swept through U.S. dairy herds in early 2024, it did something veterinarians had never seen before. Instead of targeting the respiratory system like it does in other mammals, the virus attacked the udders with vicious intensity, causing severe inflammation and tissue damage. The mystery left the field scrambling.
Now researchers at the University of Pittsburgh School of Public Health have identified exactly why. The answer lies in how the virus binds to cells, and it could reshape how scientists prepare for H5N1's next move into new animal populations.
The outbreak started in the Texas Panhandle, where cattle developed necrotizing mastitis, a painful disease that destroys mammary gland tissue. Veterinarians were initially baffled because they expected to find bacterial pathogens, not a bird virus.
"When the real culprit turned out to be bird flu, everyone in the field was caught completely by surprise," said Suresh Kuchipudi, chair of Infectious Diseases and Microbiology at Pitt Public Health. "We hadn't even remotely considered that cattle could be a host for H5N1."
Before identification, the virus spread rapidly among dairy herds. Infected cows shed high amounts of virus into their milk, raising occupational risks for farm workers and concerns about raw milk consumption. Some cats that ingested unpasteurized milk from infected animals died.
The biological puzzle centered on receptor biology. Influenza viruses attach to specific receptors on cell surfaces like a lock fitting into a key. These receptors are sugar-based molecules called glycans. Previous research had found flu glycan receptors in the noses, tracheas, and lungs of cattle, yet infected cows weren't developing respiratory disease. Something didn't add up.
Kuchipudi partnered with Harvard Medical School researcher Lauren E. Pepi, a glycomics specialist, to map out the detailed architecture of how H5N1 binds to cattle tissue. The team used binding experiments, staining techniques, and ultra-high-resolution imaging to examine the virus's interactions with different tissues.
What they discovered was subtle but decisive. Not all glycan receptors are created equal. H5N1 could only bind to a specific subtype called N-linked sialic acid receptors. These receptors were abundant throughout udder tissue but nearly absent in airway tissue.
"The mammary glands became a perfect breeding ground for the virus," Kuchipudi explained. That distribution explained why cattle developed severe mastitis instead of respiratory illness.
The implications extend far beyond dairy farms. The same mapping technique could help scientists identify which animals and tissues are vulnerable to H5N1 before outbreaks occur, rather than scrambling to respond after the fact.
"We can preemptively screen different species and different tissues within them for susceptibility," Kuchipudi said. "For example, would they exhibit respiratory symptoms? Would they show only mastitis, as in cows? Or would they show neurological disease, as we've seen in cats? The lessons learned could potentially help prevent us from being caught by surprise again."
The study, published in Science Advances, was supported by Pitt Public Health and the U.S. Department of Agriculture's National Institute of Food and Agriculture.
Author Jessica Williams: "This is the kind of detective work that turns a crisis into preparation, but it also reveals how much we still don't know about where H5N1 will pop up next."
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