Influenza A viruses (IAVs) demonstrate notable adaptability to new host species. This adaptability has long been attributed to the specificity of the viral hemagglutinin (HA) for sialylated glycans and to the functional interplay between HA and neuraminidase (NA). The traditional model emphasized sialic acids on cell-surface glycans and glycosphingolipids as the principal determinants of viral entry, tissue tropism, and species barriers.
For decades, sialic acids presented on N- and O-linked glycans and on glycosphingolipids were considered the only relevant receptors for IAV attachment and internalization. HA binding to these sialylated glycoconjugates has been central to understanding viral tropism and species specificity, with the HA–NA balance shaping efficient entry and release.
This receptor-centric view was challenged by the discovery of bat-derived H17N10 and H18N11 viruses and the subsequent identification of an avian H19 subtype. These subtypes do not rely on sialic acid binding for entry. Instead, they use major histocompatibility complex class II (MHC‑II) molecules as entry receptors. This finding established that alternative, proteinaceous receptors can mediate IAV entry independently of sialylated glycans.
Recent experimental work has shown that certain H2N2 and H3N2 viruses display dual receptor specificity, engaging both sialic acids and MHC‑II molecules. This dual engagement expands the conceptual landscape of IAV receptor usage beyond a single-receptor paradigm and indicates that canonical human and avian subtypes may access alternative entry routes under some circumstances.
The review integrates structural data to compare how HA engages sialic acids versus how HA variants interact with MHC‑II. It highlights determinants within HA that govern glycan specificity and the molecular interfaces that enable MHC‑II recognition. These structural insights help explain how receptor binding can shift between glycan-dependent and proteinaceous targets.
A central theme is the plasticity of the HA receptor‑binding site. Mutations and structural variation in HA can alter binding preferences, facilitating either exclusive sialic acid binding, exclusive MHC‑II binding, or a mixed phenotype with dual specificity. This plasticity underlies the capacity of IAVs to adapt receptor usage as they cross species barriers or encounter different cellular environments.
Differences in receptor usage have practical consequences for host range and zoonotic potential. Exclusive sialic acid usage versus exclusive MHC‑II usage or dual usage will influence which cell types and tissues are targeted, the ease with which viruses cross species barriers, and the epidemiological patterns of infection. Dual receptor specificity in established subtypes suggests additional pathways for adaptation that could affect zoonotic emergence.
Switching to MHC‑II engagement shifts cellular tropism toward antigen‑presenting cells and intestinal immune niches. This redirection may alter virus–host interactions, including immune exposure and localized replication environments. The review emphasizes that tropism for MHC‑II-expressing cells represents a distinct ecological niche compared with canonical epithelial cell infection mediated by sialic acid recognition.
MHC‑II–mediated entry may relax selective constraints on NA function because reliance on sialic acid cleavage for release and spread could be reduced if entry is mediated by protein receptors. The review discusses how shifts in receptor usage could change the evolutionary pressures acting on NA and, by extension, on the HA–NA functional balance that is central to viral fitness.
By integrating classical glycan-based models and emerging data on MHC‑II-mediated entry, the review updates the receptor landscape for IAVs. The identification of alternative and dual receptor usage has implications for understanding host range, zoonotic risk, and viral evolution. The findings suggest that surveillance and mechanistic research should account for both glycan and proteinaceous receptor interactions when assessing IAV emergence and adaptation.