The avian and human influenza A virus receptors sialic acid (SA)-α2,3 and SA-α2,6 are widely expressed in the bovine mammary gland

Abstract

An outbreak of H5N1 highly pathogenic influenza A virus (HPIAV) has been detected in dairy cows in the United States. Influenza A virus (IAV) is a negative-sense, single-stranded, RNA virus that has not previously been associated with widespread infection in cattle. As such, cattle are an extremely under-studied domestic IAV host species. IAV receptors on host cells are sialic acids (SAs) that are bound to galactose in either an α2,3 or α2,6 linkage. Human IAVs preferentially bind SA-α2,6 (human receptor), whereas avian IAVs have a preference for α2,3 (avian receptor). The avian receptor can further be divided into two receptors: IAVs isolated from chickens generally bind more tightly to SA-α2,3-Gal-β1,4 (chicken receptor), whereas IAVs isolated from duck to SA-α2,3-Gal-β1,3 (duck receptor). We found all receptors were expressed, to a different degree, in the mammary gland, respiratory tract, and cerebrum of beef and/or dairy cattle. The duck and human IAV receptors were widely expressed in the bovine mammary gland, whereas the chicken receptor dominated the respiratory tract. In general, only a low expression of IAV receptors was observed in the neurons of the cerebrum. These results provide a mechanistic rationale for the high levels of H5N1 virus reported in infected bovine milk and show cattle have the potential to act as a mixing vessel for novel IAV generation.

Detection of A(H5N1) influenza virus nucleic acid in retail pasteurized milk

“…Notably, mutation analyses conducted on cattle and feline samples positive for A(H5N1), revealed amino acid sites associated with mammalian adaptation and a greater a nity for human-type receptors 2,18 . These results combined with reports of co-expression of human and avian receptors in the mammary glands of infected dairy cattle 23 , highlight the potential role of cattle as mixing vessels for zoonotic IAVs. Questions remain regarding infected dairy cattle as a source of IAV infection for susceptible, unprotected hosts who are directly or indirectly exposed to milk or secretions.…”

A single mutation in dairy cow-associated H5N1 viruses increases receptor binding breadth

“…Our glycan binding data shows that 2.3.4.4b H5N1 viruses, including those related to the ongoing dairy cow outbreak, have not gained binding to α2,6 sialic acids, the most abundant human receptor for influenza viruses, despite the presence of α2,6 sialic acids within the cow mammary glands 17,18 . Two mutations, E190D and G225D, are defined mutations for receptor switches between α2,3 and α2,6 sialic acid-linked glycans 22 .…”

“…The influenza virus preference for α2,3 or α2,6 sialic acid linkages creates a major species barrier for avian influenza viruses to spill over into humans. Two recent studies show that dairy cow mammary tissue, and particularly the mammary alveoli, has abundant α2,3 sialic acid linked glycans 17,18 . Moreover, dairy cow mammary tissues also have α2,6 sialic acid linked glycans 17,18 , suggesting dairy cow mammary glands could be a site of viral evolution to adapt H5N1 to human-like receptors.…”

Panzootic HPAIV H5 and risks to novel mammalian hosts

“…In addition, H5N1-RNA has been detected in wastewater 28 , but the source of contamination remains unknown. Importantly, recent research has raised concerns that cattle, once considered a resilient host, may act as a novel IAV host in the future and after further adaptation of H5N1 29 . A recent preprint reports that both avian and npj Viruses | (2024) 2: 22human IAV receptors to be present in the upper respiratory tract of cattle and at high densities in bovine udder tissues 29 .…”

“…Importantly, recent research has raised concerns that cattle, once considered a resilient host, may act as a novel IAV host in the future and after further adaptation of H5N1 29 . A recent preprint reports that both avian and npj Viruses | (2024) 2: 22human IAV receptors to be present in the upper respiratory tract of cattle and at high densities in bovine udder tissues 29 . These results were used to consider the risk of cows being a "mixing vessel" as known in pigs and fur animals.…”