The receptor landscape of influenza A viruses

Influenza A viruses (IAVs) have a remarkable ability to adapt to new host species, which has been attributed to the specificity of the viral hemagglutinin (HA) for sialylated glycans and the functional balance between HA and the viral neuraminidase (NA). For decades, sialic acids on N- and O-linked glycans and glycosphingolipids were considered the only receptors that govern IAV entry, tropism, and species specificity. However, the discovery of bat-derived H17N10 and H18N11 viruses, followed by the identification of an avian H19 subtype, has fundamentally challenged this concept. These viruses use major histocompatibility complex class II (MHC-II) molecules as entry receptors independent of sialic acid binding. Moreover, recent studies demonstrate that certain H2N2 and H3N2 viruses exhibit dual receptor specificity, engaging both sialic acids and MHC-II, thereby expanding the conceptual understanding of IAV receptor usage. In this review, we discuss the evolving landscape of IAV receptor specificity by integrating classical insights on glycan-dependent attachment with emerging data on MHC-II-mediated entry. We discuss the structural determinants of sialic acid and MHC-II receptor engagement, the plasticity of HA receptor-binding sites, and the consequences of exclusive or dual receptor usage on host range and zoonotic potential. We further examine how MHC-II tropism shifts cellular targeting toward antigen-presenting cells and intestinal immune niches, and how this shift may relax selective constraints on NA function.