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The interplay of cellular determinants shapes human and avian influenza A virus tropism in the airway epithelium

ABSTRACT: Influenza A viruses (IAVs) pose a persistent threat to human health through seasonal epidemics and zoonotic spillover from avian reservoirs. As respiratory pathogens, they primarily target the airway epithelium. However, how host cell-specific barriers jointly shape viral tropism and replication in primary human airway cultures remains unclear. Here, we show that avian IAVs can infect ciliated and secretory cells but preferentially bind to ciliated cells, consistent with higher abundance of their receptor α2,3-linked sialic acids, specifically sialyl Lewis X glycans, present on the apical surface of ciliated cells. Replication levels were comparable between secretory and ciliated cells in the avian strain, resulting in an overall preference for ciliated cells. In contrast, human IAVs also preferentially bind to ciliated cells but independently of α2,6-linked sialic acid abundance. Human IAVs replicate more efficiently than avian IAVs due to their ability to utilize human ANP32 proteins, but they also exhibit cell type–specific differences, with higher viral RNA levels in secretory cells. Thus, preferential binding to ciliated cells coupled with enhanced replication in secretory cells equalizes overall infection levels across cell types for human IAVs. Together, our findings highlight the spatiotemporal complexity and interplay of IAV infection dynamics in the airway epithelium and redefine current models of influenza A virus tropism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328834 | GEO | 2026/08/27

REPOSITORIES: GEO

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