Exploring influenza A virus receptor distribution in the lactating mammary gland of domesticated livestock and in human breast tissue

Authors: NELLI, RAHUL - Iowa State University; HARM, TYLER - Iowa State University; Arruda, Bailey; SIEPKER, CHRIS - Iowa State University; FASINA, OLUFEMI - Iowa State University; GROELTZ-THRUSH, JENNIFER - Iowa State University; Baker, Amy; PHILLIPS, RACHEL - Iowa State University; JONES, BRIANNA - Iowa State University; ESPINA, VIRGINIA - George Mason University; SEGER, HANNAH - Oak Ridge Institute For Science And Education (ORISE); PLUMMER, PAUL - Iowa State University; TODD, BELL - Iowa State University

Submitted to: Journal of Dairy Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/28/2025
Publication Date: N/A
Citation: N/A

Interpretive Summary: The spread of the highly pathogenic avian influenza (HPAI) virus in dairy cattle, particularly affecting the mammary glands, highlights the adaptability of influenza A viruses (IAV) to infect non-traditional species. Mammals like pigs, sheep, goats, and camelids contribute >30 billion annually to the U.S. economy and are a source of meat and milk for millions highlighting the importance of understanding viral susceptibility in these species. The presence of IAV receptors in the mammary gland of pigs, sheep, goats, and alpacas has not been explored until now. The current study used lectin histochemistry labeling and found that the mammary glands of all species were rich in receptors essential for mammalian-adapted IAV binding. Additionally, avian-adapted IAV receptors were found in all species, although to a lesser extent. These findings provide crucial insights into the potential for HPAI H5N1 to infect the mammary gland of these production animals.

Technical Abstract: The spread of the highly pathogenic avian influenza (HPAI) H5N1 virus in dairy cattle, particularly affecting the mammary glands, highlights the adaptability of influenza A viruses (IAV) to infect non-traditional species. Mammals like pigs, sheep, goats, and camelids contribute >30 billion annually to the U.S. economy and are a source of meat and milk for millions highlighting the importance of understanding viral susceptibility in these species. The zoonotic transmission of HPAI H5N1 to several dairy farmer workers and poultry workers associated with farm outbreaks is also a cause for public health concern. While sialic acid (SA) receptors that IAV targets have been identified in dairy cattle mammary glands, their presence in pigs, sheep, goats, and alpacas has not been explored until now. The current study used lectin histochemistry labeling with fluorescently labeled Sambucus nigra (SA a2,6-Gal receptors) and Maackia amurensis (SA a2,3-Gal receptors) and found that the mammary glands of all of these species, including human breast, were rich in SA a2,6-Gal receptors essential for mammalian-adapted IAV binding. Additionally, SA a2,3-Gal receptors were found in all species, although to a lesser extent in examined tissues. Among the less prevalent SA a2,3-Gal receptors, ß-(1-3) N-Acetylgalactosamine (GalNAc) receptors with an affinity towards IAVs originating from duck were more abundant than ß-(1-4) N-Acetylglucosamine (GlcNAc). Importantly, the virus implicated in the current outbreak in dairy cattle, HPAI A(H5N1) clade 2.3.4.4b was found to bind to both ruminant (cattle) and non-ruminant (pig) species. These findings provide crucial insights into the potential for HPAI H5N1 to infect and spread within the mammary glands of these production animals and humans.