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The mechanisms by which these viruses adapt to mammalian hosts while maintaining a broad avian tropism remain poorly understood. Here, we demonstrate that two naturally occurring mutations (K222Q and S227R) in the hemagglutinin (HA) of a human-infecting H5N8 strain, first identified in 2020, enhance binding affinity for both \u03b12-6-linked and Sialyl Lewis\n                    <jats:sup>X<\/jats:sup>\n                    (SLe\n                    <jats:sup>X<\/jats:sup>\n                    ) glycans, which may underlie the broad tissue binding and cross-species potential. Structural analyses reveal that these mutations expand receptor specificity for these glycans, which are abundant in the human respiratory tract and duck trachea, providing a possible molecular basis for cross-species transmission. Our findings suggest that clade 2.3.4.4b H5Ny viruses evolved dual receptor specificity as early as the 2020 Russian H5N8 strain, potentially contributing to sporadic human infections and widespread dissemination among birds and mammals.\n                  <\/jats:p>","DOI":"10.1038\/s44319-026-00816-2","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T10:37:46Z","timestamp":1781606266000},"page":"4079-4099","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hemagglutinin double-mutation enhances binding of human-infecting avian influenza virus clade 2.3.4.4b H5Ny to human and SLeX receptors"],"prefix":"10.1038","volume":"27","author":[{"given":"Xiyue","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2661-1347","authenticated-orcid":false,"given":"Haichen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunge","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2740-9098","authenticated-orcid":false,"given":"Antonio","family":"Di Maio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianjiao","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-4732","authenticated-orcid":false,"given":"Jianxun","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhai","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0101-0695","authenticated-orcid":false,"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2566-6867","authenticated-orcid":false,"given":"Yan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-0370","authenticated-orcid":false,"given":"Hao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3869-615X","authenticated-orcid":false,"given":"George F","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"816_CR64","doi-asserted-by":"crossref","unstructured":"Adams PD, Afonine PV, Bunk\u00f3czi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW et al (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. 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