Why Bird Flu Targets Cows’ Udders Instead of Lungs

In 2024, dairy cattle in northern Texas’s panhandle region suffered from a sudden illness. The milk that affected cows produced was thick and creamy yellow. The animals’ postmortem examination showed signs of mastitis, an inflammatory condition that damages mammary gland tissues.¹

“Mastitis is a classic disease in milk-production animals, and veterinarians were dutifully looking to all the usual suspects for the source, like bacterial pathogens,” said Suresh Kuchipudi, a veterinary microbiologist at the University of Pittsburgh in a statement.

However, deeper investigations of the affected animals’ milk, serum, and tissue samples revealed an unlikely suspect: an H5N1 strain of the highly pathogenic avian influenza A virus, which causes bird flu. “When the real culprit turned out to be bird flu, everyone in the field was caught completely by surprise. We hadn't even remotely considered that cattle could be a host for H5N1,” said Kuchipudi. One of the most striking observations was that instead of affecting the lungs like it does in other mammals, H5N1 targeted the cows’ mammary glands.

Now, Kuchipudi and his colleagues employed mass spectrometry, advanced microscopy, and viral binding assays to uncover the mechanism behind this unusual infectivity of H5N1 in cows.² They observed that mammary glands, but not respiratory tissues, of cattle contained a receptor that binds to the virus, providing an infection route. Their findings, published today in Science Advances, offer a framework to investigate the virus’s infectivity as it continues to run rampant in other farm animals.

Kuchipudi and his team focused on a subset of receptors containing sugar-based molecules, or glycans, which are known to bind to influenza viruses. Mass spectrometry-based glycomic profiling of bovine respiratory tissues indicated that these receptors were virtually absent in these samples, but they were present in mammary glands, making these tissues a “perfect breeding ground for the virus,” Kuchipudi said.

The researchers next carried out binding assays with a pseudovirus containing the H5N1 viral envelope but not its genetic elements, which would allow the virus to bind to the host receptor but not replicate within host cells. Electron microscopy revealed that the pseudovirus did not bind to bovine respiratory tissue but did attach to epithelial cells that line mammary glands.

Consistent with this, wild type H5N1 bound to mammary gland cells but not respiratory tissues, further validating that the receptor landscape in bovine mammary glands provides an entry route to the virus for infection.

According to Kuchipudi, these results pave the way for other scientists to identify tissues in other animals that could be susceptible to H5N1 infection. “The lessons learned could potentially help prevent us from being caught by surprise again,” he said.