Why H5N1 Bird Flu Targets Cow Udders Instead of Lungs

Bird flu is a zoonotic disease caused by the influenza A virus. As the name suggests, it primarily affects birds and, depending on the virus subtype driving the disease, can have extreme consequences. Specifically, the H5N1 virus subtype is highly pathogenic, has a high mortality rate, and has led to numerous outbreaks since it was first identified (Charostad et al. 2023).

Not only does bird flu have the potential to significantly impact food security and cause economic strain on farmers through the death and culling of infected poultry, but the infection can also transmit to humans and other animals, leading to illness and, in some cases, death.

In humans, bird flu initially presents similarly to seasonal influenza, with symptoms such as fever, sore throat, and cough, but can rapidly progress to respiratory failure (Tripathi et al. 2025).

Curiously, bird flu has recently been found to infect cows, but not in the way researchers would expect.

This blog examines recent research on why bird flu, which affects the lungs in most mammals, appears in the udders of cows.

A Mysterious Bird Flu Outbreak in Dairy Cows

In 2024, a mysterious illness began to spread amongst dairy cows in northern Texas. Affected cattle displayed a lack of appetite and reduced milk production. In addition, the quality of the little milk that the animals managed to produce was severely impacted, being overly thick and yellow in appearance.

This illness then reared its head in cattle farms in southwestern Kansas and northeastern New Mexico.

A common cause of reduced milk production and quality in cows is mastitis, inflammation of the udder, which is commonly caused by bacterial infections. Researchers were, therefore, puzzled to find that samples from the sick cows were negative for the common bacterial perpetrators.

But the scientists caught a break in the case, with a strong piece of evidence pointing towards the likely culprit: the death of wild birds in the area.

Upon testing, the researchers realized that the cows were positive for bird flu, an unexpected twist, as up until this point, cows were believed to be resistant to influenza A infection (Sreenivasan et al. 2019).  And stranger still that the infection would affect the udders of cows (Burrough et al. 2024).

How Glycan Receptors Help Explain H5N1 Infection in Cow Udders

So, with this intriguing case of cows positive for bird flu presenting with mastitis and very little, if any, respiratory involvement, Srinivas et al. (2026) set out to untangle the mystery.

The ability of a virus to infect specific cells or tissues of the host depends on whether the target cell expresses protein receptors on its surface that the virus can bind to.

Different strains of influenza virus have preferences for certain structures. For example, factors such as sialylation—the addition of sialic acid— or glycosylation—the addition of a glycan—of a receptor can determine binding.

On top of that, the type of glycosylation can also impact the virus's ability to attach to a receptor. Glycosylation subtypes are determined by which amino acid in the protein the glycan is attached to; N-linked glycans are attached to asparagine while O-linked glycans are attached to serine or threonine (Dell et al. 2011).

So, to understand why H5N1 affects the udders of cows more than the lungs, the scientists conducted experiments to uncover the glycan profile displayed by epithelial cells from the mammary gland and trachea.

Comparing Glycan Receptors in Cow Udders and Airways

They found that the mammary gland contained an abundance of both N-linked and O-linked sialylated glycans, while the tracheal epithelium exhibited only O-linked sialylated glycans. The lack of N-linked sialylated glycans is notable given their known role in the attachment of influenza viruses.

To confirm that the identified receptors were actually anatomically accessible to the virus, the researchers performed binding assays using a pseudovirus, which has the surface proteins of the H5N1 virus but not the genetic material of the viral core—so the virus can infect the cells but not replicate.

Using scanning electron microscopy (SEM), the scientists observed significant surface binding of the pseudovirus to the mammary epithelium but minimal binding to the tracheal epithelium.

What This Discovery Could Mean for Future Bird Flu Outbreaks

In this study, Srinivas et al. were able to assign a molecular explanation to the predisposition of the H5N1 virus to infect the udders of cows rather than the respiratory tract.

The authors state that this could provide a proactive approach to determining susceptibility of other mammals and which tissue may be most at risk of bird flu infection, enabling the development of strategies to limit spread and prepare for future outbreaks.