An emerging PB2-627 polymorphism increases the zoonotic risk of avian influenza virus by overcoming ANP32 host restriction in mammalian and avian hosts

作者：Yuxin Guo, Sicheng Shu, Yong Zhou, Wenjing Peng, Zhimin Jiang, Yudong Li, Tian Li, Fanshu Du, Linlin Wang, Xue Chen, Jinze Dong, Chuankuo Zhao, Maggie Haitian Wang, Yipeng Sun, Honglei Sun, Lu Lu, Paul Digard, Kin‐Chow Chang, Hui‐Ling Yen, Jinhua Liu, Juan Pu · 发表于：Journal of Virology · 年份：2025 · DOI：10.1128/jvi.00853-25 · 被引用次数：6 · 研究领域：Influenza Virus Research Studies、Viral Infections and Vectors、Viral gastroenteritis research and epidemiology

Alterations in the PB2-627 domain of avian influenza virus (AIV) can potentially increase the risk of cross-host species infections in humans and mammals. Recently, there has been a rise in human cases of AIV infections without the presence of the known mammalian determinant PB2-E627K. Here, we identified a variant, PB2-627V, which has evolved in poultry and has contributed to the increase in human AIV infections. By screening global PB2 sequences, we discovered a new independent cluster of PB2-627V that emerged in the 2010s, prevalent in avian, mammalian, and human AIV isolates, including those of H9N2, H7N9, H3N8, 2.3.4.4b H5N1, and other subtypes. We functionally assessed its host adaptation, fitness, and transmissibility across three subtypes of AIVs (H9N2, H7N9, and H3N8) in different host models. PB2-627V combines the viral properties of avian-like PB2-627E and human-like PB2-627K, facilitating AIVs to efficiently infect and replicate in chickens and mice by utilizing both avian- and human-origin ANP32A proteins. Importantly, PB2-627V promotes efficient transmission between ferrets through respiratory droplets. Deep sequencing of passaged chicken and transmitted ferret viral samples indicates that PB2-627V remains stable across the two host species and shows a high potential for long-term prevalence in avian species. Thus, the PB2-627V mutation in AIVs can stably transmit through poultry and can overcome the cross-species barrier to infect humans. Given the global promi...