{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:06:40Z","timestamp":1779253600465,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The hemagglutinin (HA) of influenza A\/H3N2 virus evolves rapidly, with glycosylation driving immune evasion. However, how host microenvironmental cues influence this process remains poorly understood. We identified a novel N-linked glycosylation site at position 110 (N110) in contemporary H3N2 viruses (NSS genotype) that enhances viral fitness by increasing receptor-binding signal, HA cleavage, and replication. Remarkably, hypoxia, which mimics the respiratory tract microenvironment, significantly augments N110 glycosylation. Mechanistically, we identified the B4GAT1-B4GALT1 complex as the key mediator of this modification. Hypoxia upregulates their expression and strengthens their interaction with HA. In ferret models, N110-glycosylated viruses exhibit heightened pathogenicity and evade ancestral antibodies. Furthermore, immunization with N110-containing HA confers broad-spectrum protection, whereas reciprocal immunization is ineffective. Our findings reveal hypoxia-driven glycosylation as a previously unrecognized mechanism of H3N2 adaptation, providing critical insights for vaccine efficacy and highlighting the importance of integrating microenvironmental factors into future antiviral strategies.<\/jats:p>","DOI":"10.3390\/v18050547","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:11:13Z","timestamp":1778271073000},"page":"547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia-Enhanced N110 Glycosylation of Hemagglutinin Promotes H3N2 Influenza Virus Fitness by Modulating Receptor Binding and Immune Evasion"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9502-9441","authenticated-orcid":false,"given":"Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihui","family":"Fang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1445-448X","authenticated-orcid":false,"given":"Bin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5039-0348","authenticated-orcid":false,"given":"Yanan","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihua","family":"Ding","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinong","family":"Ye","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing 100071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/s12276-021-00603-0","article-title":"The evolution and future of influenza pandemic preparedness","volume":"53","author":"Harrington","year":"2021","journal-title":"Exp. 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