Distribution of influenza A virus receptors in tissues of South American marine wildlife.

H5 clade 2.3.4.4b high pathogenicity avian influenza viruses (HPAIVs) have caused unprecedented mortality in marine wildlife. However, host determinants of susceptibility to influenza A virus (IAV) infection remain poorly understood. IAVs adapted to different hosts show distinct binding preferences for different kinds of sialic acid (Sia) receptors on cell surfaces. Human‑adapted IAVs preferentially bind Sia α2,6-linked glycans, while avian‑adapted viruses prefer Sia α2,3-linked glycans. We characterized the distribution of α2,6- and α2,3-linked Sia, and fucosylated or sulfated Siaα2,3 across respiratory, intestinal, and neural tissues from stranded marine animals, including two South American sea lions (Otaria flavescens), a Burmeister's porpoise (Phocoena spinipinnis), and a Magellanic penguin (Spheniscus magellanicus). We also compared binding patterns of recombinant hemagglutinins (rHAs) derived from a classical H5 clade 1 virus and contemporary clade 2.3.4.4b viruses in the same tissues. We detected widespread expression of Sia receptors and H5 rHA binding in bronchial and alveolar epithelium (including air capillaries of the penguin) of the lung, enterocytes and goblet cells of intestinal villi, and the meninges and vascular endothelium of neural tissues, with species‑ and tissue‑specific patterns. These findings indicate that marine mammals and penguins possess receptor landscapes compatible with infection by both classical and contemporary H5 HPAIVs. Further investigation is necessary to determine how receptor distribution relates to productive replication, respiratory or fecal shedding, and cross-species transmission risk, particularly given the pronounced neurotropism and peracute disease course associated with clade 2.3.4.4b viruses.