Global evolutionary landscape of H11 avian influenza and initial isolates identified in Xinjiang, China

H11 avian influenza viruses (AIVs) circulate globally among wild bird populations, yet their evolutionary pathways and risks for zoonotic transmission remain insufficiently characterized. In the current study, analysis of 1,179 H11 hemagglutinin (HA) sequences revealed that dispersal patterns closely follow Eurasian migratory flyways, with Xinjiang identified as a seasonal transit and amplification node. From 2,674 wild-bird samples, two viruses – K77/H11N2 and BL0/H11N3 – were isolated (2/2674, approximately 0.07%). Genomic analyses positioned both viruses within Eurasian wild-bird lineages, exhibiting broad relatedness to AIVs from South Asia, East Asia, Europe, and Antarctica. HA profiles indicated a predominant avian receptor affinity; notably, K77/H11N2 exhibited prominent α2,3 binding as well as weaker, concentration-dependent α2,6 binding, and harboured putative mammalian-adaptive markers PB2-I292V and NP-52H/313F, suggesting potential for enhanced viral fitness in mammalian cells. These markers were absent in BL0/H11N3. In vitro and in vivo analyses revealed greater HA stability, moderate replication in A549 cells, and localized lung inflammation in mice for K77/H11N2, while BL0/H11N3 demonstrated limited replication and minimal pathogenicity. Both viruses achieved systemic dissemination and direct-contact transmission among chickens, corresponding to high poultry seroprevalence rates (up to 65%). Antibodies detected in cattle (3.8%) and camels (∼2%) on farms near migratory-bird habitats provide rare evidence of natural H11 exposure in mammals. Collectively, this study presents the first comprehensive genomic and phenotypic characterization of H11 viruses detected in Xinjiang, underscoring the emergence of an H11N2 strain with limited mammalian adaptation and highlighting the need for intensified surveillance at the wildlife–poultry–livestock interface.