When H5N1 avian influenza began infecting dairy cows in the United States in early 2024, veterinarians struggled to pinpoint the cause. The virus has been difficult to recognize because it behaves very differently in cattle than in other mammals. Rather than primarily infecting the lungs, H5N1 causes severe infections in the breasts, but has little effect on the respiratory system.
Now, researchers at the University of Pittsburgh School of Public Health have uncovered the biological reason behind this unusual pattern. Their findings were; scientific progressfor the first time we have a detailed explanation of why avian influenza took such an unexpected shape in cattle. The study could also help scientists better predict how H5N1 will behave if it spreads to new animal species in the future.
Unusual occurrence of avian influenza in dairy herds
The outbreak first occurred in dairy cows in the Texas Panhandle, where severe cases of necrotizing mastitis, a painful inflammatory disease that damages mammary gland tissue, developed.
“Mastitis is a classic disease of milk-producing animals, and veterinarians were dutifully investigating all the common causes, including bacterial pathogens,” said lead author Dr. Suresh Kuchipudi, chief of infectious diseases and microbiology at Pitt Public Health. “Everyone on the scene was completely surprised when the real culprit turned out to be avian influenza. We never had the slightest idea that cows could be a host for H5N1.”
Before the virus was identified, it spread from herd to herd, infecting cattle and contaminating their surroundings.
“When a cow is infected, a large amount of virus is shed in the milk,” Kuchipudi said. “This has raised concerns about occupational risks for farm workers, and the practice of feeding raw milk to pets such as cats, which in some cases has resulted in cat deaths, which we have previously investigated.”
Kuchipudi said pasteurization effectively destroys viruses and stressed the importance of avoiding raw milk.
Look for a biological explanation
Throughout her career, Kuchipudi has studied influenza viruses, focusing on how their receptor biology affects the species and tissues they infect. Influenza viruses attach to specific receptors on cells in a lock-and-key manner. These receptors belong to a group of sugar-based molecules known as glycans.
Previous studies by other research groups suggested that glycan receptors associated with influenza are present in cows’ noses, tracheas, and lungs. However, the cows infected with H5N1 did not develop the respiratory disease the researchers expected.
This discrepancy suggests that a more detailed explanation is needed.
“Glycan biology is very complex,” Kuchipudi says. “We realized that to understand what was actually going on, we needed to use more innovative techniques and map out the detailed structures that allow the virus to bind to cells.”
To do so, Kuchipudi partnered with Dr. Lauren E. Pepi, a researcher at Harvard Medical School who specializes in glycomics, the comprehensive study of glycan structures.
Why H5N1 targets cow udders
The research team combined multiple techniques, including binding experiments, staining techniques, and ultra-high-resolution imaging, to examine how H5N1 interacts with different tissues.
Their analysis showed that not all glycan receptors function the same way when it comes to avian influenza infection. The virus was only able to bind to a specific subtype known as N-linked sialic acid receptors.
These receptors were found throughout bovine mammary tissue, but were largely absent from airway tissue. This made the mammary glands “the perfect breeding ground for the virus,” Kuchipudi said.
This finding helps explain why H5N1 caused severe mastitis rather than respiratory disease in dairy cows.
Predicting the next move of bird flu
The researchers believe their findings could do more than explain the occurrence in cattle. The same approach could help scientists identify which animals and tissues are vulnerable to H5N1 before future outbreaks occur.
“We can pre-screen the susceptibility of different species and different tissues within them,” Kuchipudi said. “For example, will they show respiratory symptoms? Will they show only mastitis, like cows? Or will they show neurological disease, as our team has shown in cats? The lessons learned could help us avoid being caught by surprise again.”
Other authors of the study are Surabhi Srinivas, Ph.D., Shubhada K. Chothe, Ph.D., Santhamani Ramasamy, Ph.D., Sougat Misra, Ph.D., Noel Chandan Nallipogu, MD, MPH, Lindsey LaBella, all of Pitt. Yingting Yeh, Ph.D., Penn State University; Mei Wang, Bachelor of Science, Harvard University; Dr. Heidi L. Pecoraro and Dr. Brett T. Webb of North Dakota State University;
This research was supported by Pitt Public Health and the USDA National Institute of Food and Agriculture (FP00039373/AWD00010780).
