Abstract The H5N1 high pathogenicity avian influenza virus (HPAIV) of clade 2.3.4.4b, which spreads globally via wild birds , has become a major public health concern because it can infect a variety of mammals , including humans . In 2024, infection of dairy cattle with H5N1 HPAIV clade 2.3.4.4b was confirmed in the United States , and subsequent human cases were reported. Although these viruses are highly pathogenic in animal models , human infections have generally been mild , revealing a striking discrepancy . Here, we characterized the cattle-derived human H5N1 isolate A/Texas/37/2024 (TX37-H5N1) using three-dimensional human respiratory organoids derived from induced pluripotent stem (iPS) cells. Despite efficient replication , TX37-H5N1 induced minimal interferon and inflammatory cytokine responses . Bulk and single-cell RNA sequencing revealed reduced STAT1-mediated transcriptional activity in TX37-H5N1-infected organoids compared to the historic H5N1 human isolate A/Vietn...