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

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 nontraditional species. Mammals like pigs, sheep, goats, and camelids contribute >$30 billion annually to the US 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 and poultry farm workers involved with farm operations during outbreaks is also a cause for public health concerns. Previous studies showed IAV-specific sialic acid (SA) receptors in the mammary glands of dairy cattle, but those studies did not explore their presence in pigs, sheep, goats, alpacas, and humans. The current study used lectin histochemistry staining with fluorescently labeled Sambucus nigra (SA α2,6-galactose [gal] receptors) and Maackia amurensis (SA α2,3-gal receptors) and found that the mammary glands of all of these species, including human breast, were rich in SA α2,6-gal receptors essential for mammalian-adapted IAV binding. We also found SA α2,3-gal receptors in the examined tissues of all species, although to a lesser extent. Notably, an A(H5N1) clade 2.3.4.4b virus demonstrated binding to both ruminant (cattle) and nonruminant (pigs) species' mammary tissue. These findings provide crucial insights into the potential for HPAI H5N1 to infect and spread within the mammary glands of these production animals, as well as humans.