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Adv."],"published-print":{"date-parts":[[2026,6,19]]},"abstract":"<jats:p>The unusual tropism of H5N1 clade 2.3.4.4b for cattle mammary glands, causing necrotizing mastitis without major respiratory involvement, raises critical questions about its underlying mechanisms. We conducted glycomics and linkage-specific lectin histochemistry to characterize sialic acid (SA) receptor diversity and anatomical distribution, and virus binding assays and high-resolution electron microscopy (EM) to visualize virus-receptor interactions. Cattle mammary gland exhibited an abundance of N- and O-linked SA glycans, showing a stronger binding affinity to clade 2.3.4.4b H5 than clade 2.2 H5. In contrast, the cattle trachea contained only O-linked but not N-linked SAs and showed no detectable H5 binding, indicating limited compatible influenza A virus (IAV) receptor availability in the tracheal epithelium. EM of virus-bound tissues further validated the receptor basis of H5N1 infection in cattle. As H5N1 continues infecting unusual hosts, as evidenced by the first case in sheep, our study offers a methodological framework for assessing IAV susceptibility.<\/jats:p>","DOI":"10.1126\/sciadv.aea2068","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T18:00:33Z","timestamp":1781892033000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Receptor basis of unusual tissue tropism of avian influenza H5N1 clade 2.3.4.4b virus in cattle"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4987-1985","authenticated-orcid":true,"given":"Surabhi","family":"Srinivas","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7109-7810","authenticated-orcid":true,"given":"Shubhada K.","family":"Chothe","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."},{"name":"Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2118-4681","authenticated-orcid":true,"given":"Santhamani","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."},{"name":"Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sougat","family":"Misra","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."},{"name":"Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel Chandan","family":"Nallipogu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-6166","authenticated-orcid":true,"given":"Lindsey","family":"LaBella","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."},{"name":"Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-Ting","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Physics, The Pennsylvania State University, University Park, PA 16802, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May","family":"Wang","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5740-4175","authenticated-orcid":true,"given":"Lauren E.","family":"Pepi","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5475-5482","authenticated-orcid":true,"given":"Heidi L.","family":"Pecoraro","sequence":"additional","affiliation":[{"name":"Veterinary Diagnostic Laboratory, North Dakota State University, Fargo, ND 58102, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett T.","family":"Webb","sequence":"additional","affiliation":[{"name":"Veterinary Diagnostic Laboratory, North Dakota State University, Fargo, ND 58102, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8640-254X","authenticated-orcid":true,"given":"Suresh V.","family":"Kuchipudi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA."},{"name":"Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA."},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","unstructured":"Centers for Disease Control and Prevention Current situation: Bird flu in dairy cows (2025); 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