Heterogeneous viral-host response at single-cell resolution and viral adaptive mutational atlas in birds and mammals upon H5 influenza virus infection

Abstract H5 highly pathogenic avian influenza viruses (HPAIVs) are prevalent in birds, causing infection in over 60 mammalian species worldwide. However, species-specific viral-host response at the single-cell level and within-host evolution upon H5-HPAIV infection are poorly understood. Here, by integrating spatial transcriptomics and single-cell genomics technologies, we present a comprehensive single-cell transcriptomic landscape of 1499 669 cells in the lungs from birds (chickens, ducks, and pigeons) and mammals (mice and pigs) upon H5-HPAIV infection. H5-HPAIV primarily infected avian endothelial cells and mammalian epithelial cells, respectively. Among the single-cell transcriptomic lung landscape, H5-HPAIV infection induced significant inflammation in fibroblasts and the shedding of alveolar epithelial cells of chickens upon infection, while the expression levels of cytokine- and inflammation-related genes slightly decreased in fibroblasts and endothelial cells of infected ducks and pigeons, respectively. However, mice only exhibited significantly antiviral response in macrophages and neutrophils, while antiviral response was elevated in most subtype cells of pigs upon infection. Notably, we identified 19 viral non-synonymous intrahost single nucleotide variants (iSNVs) in infected birds and mammals and assessed their molecular characterizations in vitro. Three of them were identified to increase polymerase activity and viral replication in situ, among which the PB2-E627K mutation was enriched in the alveolar structure of lungs, accompanied by elevated expression of interferon-stimulated genes. Collectively, we elucidated distinct viral replication, host response, and viral adaptation in the lungs across diverse birds and mammals upon H5-HPAIV infection.

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Publication Details

Journal
National Science Review
Published
2026-06-25
DOI
https://doi.org/10.1093/nsr/nwag380
Primary Topic
interferon and immune responses
Type
article
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article

Heterogeneous viral-host response at single-cell resolution and viral adaptive mutational atlas in birds and mammals upon H5 influenza virus infection

Jiangtao Zhou, Wenbao Qi, Huaiyuan Cai, Zhangyong Ning et al.
National Science Review
interferon and immune responses
article

Heterogeneous viral-host response at single-cell resolution and viral adaptive mutational atlas in birds and mammals upon H5 influenza virus infection

Jiangtao Zhou, Wenbao Qi, Huaiyuan Cai, Zhangyong Ning, J H Liu, Shiping Ding, X Chen, Weifeng Shi, Lihong Huang, Q Zhang, Zi Wang, Jiahao Zhang, He Zhang, Liu Y, Yuehua Chen, Li Li, Xinyu Zhuang, Weize Xu, Junlong Xiong, Xiaoshu Zhou, Weixin Jia, Jiahao Zhang, Jinxia Dai, Xiaofeng Wu, Ruixuan Zhu, Ke Xiao, Ming Liao, Tao Zhang, Hui Guo, Tingting Man, Haixing Yang
article en

Abstract

Abstract H5 highly pathogenic avian influenza viruses (HPAIVs) are prevalent in birds, causing infection in over 60 mammalian species worldwide. However, species-specific viral-host response at the single-cell level and within-host evolution upon H5-HPAIV infection are poorly understood. Here, by integrating spatial transcriptomics and single-cell genomics technologies, we present a comprehensive single-cell transcriptomic landscape of 1499 669 cells in the lungs from birds (chickens, ducks, and pigeons) and mammals (mice and pigs) upon H5-HPAIV infection. H5-HPAIV primarily infected avian endothelial cells and mammalian epithelial cells, respectively. Among the single-cell transcriptomic lung landscape, H5-HPAIV infection induced significant inflammation in fibroblasts and the shedding of alveolar epithelial cells of chickens upon infection, while the expression levels of cytokine- and inflammation-related genes slightly decreased in fibroblasts and endothelial cells of infected ducks and pigeons, respectively. However, mice only exhibited significantly antiviral response in macrophages and neutrophils, while antiviral response was elevated in most subtype cells of pigs upon infection. Notably, we identified 19 viral non-synonymous intrahost single nucleotide variants (iSNVs) in infected birds and mammals and assessed their molecular characterizations in vitro. Three of them were identified to increase polymerase activity and viral replication in situ, among which the PB2-E627K mutation was enriched in the alveolar structure of lungs, accompanied by elevated expression of interferon-stimulated genes. Collectively, we elucidated distinct viral replication, host response, and viral adaptation in the lungs across diverse birds and mammals upon H5-HPAIV infection.

National Science Review
South China Agricultural University (CN), Shanghai University (CN), Shanghai Jiao Tong University (CN), Jilin University (CN), Huazhong Agricultural University (CN), Ruijin Hospital (CN), ShanghaiTech University (CN), Guangzhou Center for Disease Control and Prevention (CN), Changchun Institute of Optics, Fine Mechanics and Physics (CN), Changchun Institute of Applied Chemistry (CN), Key Laboratory of Guangdong Province (CN), Guangdong Academy of Agricultural Sciences (CN), National Influenza Center (MN), Taiwan Centers for Disease Control (TW), Shenzhen University Health Science Center (CN), Shenzhen Institutes of Advanced Technology (CN), Ministry of Agriculture and Rural Affairs (CN), Shenzhen Technology University (CN), Institute of Special Animal and Plant Sciences (CN), Zhongkai University of Agriculture and Engineering (CN)
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