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<p>The unexpected circulation of clade 2.3.4.4b H5N1 influenza viruses in dairy cattle and the transmission to diverse mammalian species poses a pandemic risk. We sought to explore cattle and human respiratory susceptibility to the 2.3.4.4b H5N1 virus. We establish long-term expandable cattle airway and mammary organoids. The 2.3.4.4b H5N1 virus exhibits high replicative fitness in cattle mammary organoids, recapitulating its remarkable mammary tropism. The virus also replicates robustly in cattle airway organoids, suggesting an underrecognized respiratory component in ongoing outbreaks. Interestingly, human airway and nasal organoids are highly susceptible to the 2.3.4.4b H5N1 virus. Yet, a novel organoid-based neutralization assay reveals that N1 antibodies in human sera had cross-neutralizing activity against the 2.3.4.4b H5N1 and ancestral H5N1-VN1194 viruses. The cross-neutralization, exclusively manifested in the organoid-based assay, is enhanced after seasonal influenza vaccination and diminished after depleting N1-specific antibodies. Therefore, cross-neutralizing N1 antibodies are likely limiting zoonotic infection by H5N1 viruses in humans.</p>

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Cattle and human organoids reveal 2.3.4.4b H5N1 cross-species transmission potential and neuraminidase-specific neutralizing antibodies in humans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Cun Li,
  • Yifei Yu,
  • Zhixin Wan,
  • Jian-Piao Cai,
  • Jingjing Huang,
  • Xiaoxin Zhu,
  • Jiali Wu,
  • Wei Xue,
  • Ying Zhou,
  • Man Chun Chiu,
  • Qiaoshuai Lan,
  • Shuxin Zhang,
  • Zijun Zhao,
  • Yidong Yang,
  • Yuhong Liu,
  • Pui Wang,
  • Shaofeng Deng,
  • Ming Yue,
  • Longchao Zhu,
  • Keshan Zhang,
  • Mengmeng Zhao,
  • Jieshi Yu,
  • Wenkang Wei,
  • Xiang Gao,
  • Lin Huang,
  • Hin Chu,
  • Gang Wu,
  • Honglin Chen,
  • Kwok Yung Yuen,
  • Richard Webby,
  • Jie Zhou

摘要

The unexpected circulation of clade 2.3.4.4b H5N1 influenza viruses in dairy cattle and the transmission to diverse mammalian species poses a pandemic risk. We sought to explore cattle and human respiratory susceptibility to the 2.3.4.4b H5N1 virus. We establish long-term expandable cattle airway and mammary organoids. The 2.3.4.4b H5N1 virus exhibits high replicative fitness in cattle mammary organoids, recapitulating its remarkable mammary tropism. The virus also replicates robustly in cattle airway organoids, suggesting an underrecognized respiratory component in ongoing outbreaks. Interestingly, human airway and nasal organoids are highly susceptible to the 2.3.4.4b H5N1 virus. Yet, a novel organoid-based neutralization assay reveals that N1 antibodies in human sera had cross-neutralizing activity against the 2.3.4.4b H5N1 and ancestral H5N1-VN1194 viruses. The cross-neutralization, exclusively manifested in the organoid-based assay, is enhanced after seasonal influenza vaccination and diminished after depleting N1-specific antibodies. Therefore, cross-neutralizing N1 antibodies are likely limiting zoonotic infection by H5N1 viruses in humans.