The bovine mammary gland as a crucible for zoonotic influenza virus emergence: Receptor-mediated adaptation of HPAI H5N1 clade 2.3.4.4b.

The recent emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in U.S. dairy cattle marks a pivotal shift in the ecology of influenza A viruses (IAVs), signaling an unexpected expansion into a major livestock species. This review explores the molecular mechanisms underpinning this cross-species transmission, focusing on the unique sialic acid receptor landscape of the bovine mammary gland as a critical determinant. We synthesize emerging evidence that this tissue, which co-expresses both avian-type (α2,3-linked) and human-type (α2,6-linked) sialic acid receptors, functions as a novel biological crucible for viral adaptation. Within this environment, H5N1 virus faces selective pressure for hemagglutinin (HA) mutations—such as Q226L and N193D—that can alter receptor binding specificity toward human-like glycans, potentially bridging the species barrier. Recent studies confirm that bovine H5N1 virus isolates exhibit dual receptor-binding avidity and that single HA mutations are sufficient to shift binding preference to human receptors. The unprecedented mammalian spread of clade 2.3.4.4b, coupled with its capacity for reassortment and the recent case of a dairy farm worker infection, underscores an urgent zoonotic and pandemic threat. This review contextualizes the outbreak within the fundamental principles of influenza virus receptor biology and viral evolution, highlighting critical knowledge gaps that must be addressed through integrated surveillance and multidisciplinary research. Understanding the interplay between host receptor distribution and viral plasticity in this new niche is paramount for mitigating the risk of a future influenza virus pandemic emerging from the bovine reservoir.