{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:32:57Z","timestamp":1789576377020,"version":"build-2803163510"},"reference-count":54,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The pathogenicity of emerging early zoonotic avian H7N9 and H3N8 low\u2010pathogenic avian influenza viruses (LPAIVs) in humans is significantly enhanced compared to that of their internal gene providers, H9N2 avian influenza viruses (AIVs), suggesting a pivotal role for surface HA or NA. Here, we generated several reassortant AIVs that combined HA, NA, or HA\u2009+\u2009NA from emerging zoonotic H7N9 or H3N8 LPAIV with internal H9N2 AIV genes and investigated the impact of HA and NA on the replication and pathogenicity of reassortants in human cells and mice. The crucial affected phase was determined by analyzing the receptor binding, viral adsorption, HA cleavage efficiency, viral\u00a0endocytosis, and budding. We found that mice infected with the virus containing the early zoonotic H7N9 LPAIV HA, but not NA, exhibited high mortality, weight loss, severe lung damage, and increased viral load in the lungs. We found that HA substitution enhanced viral replication in human A549 cells and displayed dual sialic acid receptor binding ability. This substitution also facilitated viral attachment to mammalian cells and promoted endocytosis by enhancing HA0 cleavage efficiency; however budding was not affected. Additionally, HA from emerging zoonotic H3N8 LPAIVs elevate the pathogenicity of reassortants in mice. Together, our study revealed that HA of emerging zoonotic LPAIVs contributes to high pathogenicity in mammals by augmenting viral entry and causing lung injury, thereby highlighting HA with double receptor binding properties and HA cleavage efficiency as new markers for risk assessment of emerging zoonotic AIVs in the future.<\/jats:p>","DOI":"10.1002\/jmv.70615","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T09:02:29Z","timestamp":1758877349000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hemagglutinin of Emerging Low Pathogenic Avian Influenza Viruses Underpins High Pathogenicity to Mammals"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5499-4954","authenticated-orcid":false,"given":"Xiaoyi","family":"Gao","sequence":"first","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of avian influenza and other major poultry diseases of the Ministry of Agriculture and Rural Affairs College of Veterinary Medicine, China Agricultural University Beijing China"},{"name":"Key Laboratory of Veterinary Bioproduction and Chemical Medicine of the Ministry of Agriculture, Engineering and Technology Research Center for Beijing Veterinary Peptide Vaccine Design and Preparation Zhongmu Institute of China Animal Husbandry Industry, Co. 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Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinze","family":"Dong","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of avian influenza and other major poultry diseases of the Ministry of Agriculture and Rural Affairs College of Veterinary Medicine, China Agricultural University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, Key Laboratory for Prevention and Control of avian influenza and other major poultry diseases of the Ministry of Agriculture and Rural Affairs College of Veterinary Medicine, China Agricultural University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuankuo","family":"Zhao","sequence":"additional","affiliation":[{"name":"National 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