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Am J Respir Crit Care Med
. 2026 Mar 16:aamag122.
doi: 10.1093/ajrccm/aamag122. Online ahead of print.
A large-scale single-cell atlas reveals the pulmonary immune panorama in adult patients with influenza
Kun Xiao 1 , Yan Cao 1 , Zhihai Han 1 , Qian Da 2 , Yun Feng 3 , Rong Tian 4 , Laurence Don Wai Luu 5 6 , Li Zhang 7 , Xiaoyan Li 8 , Ruijuan Wang 9 , Qi Li 10 , Mei Hu 11 , Fucheng An 12 , Xiangxin Li 13 , Fei Zhang 14 , Shubin Qiao 15 , Qingrong Nie 16 , Ping Jiang 7 , Xia Ma 17 , Ye Hu 1 , Kaifei Wang 1 , Zhimei Duan 1 , Yang Liu 18 , Jiaxin Wang 1 , Wenjian Xu 19 , Peng Yan 20 , Xiang Gao 21 , Bin Cao 22 , Lixin Xie 1 , Yi Wang 19 23 24
Affiliations
Rationale: The host immune determinants that distinguish protective from life-threatening responses to influenza are poorly understood. Identifying drivers of immunopathology in the human lung is critical for developing potential therapies.
Objectives: To define the cellular and molecular immune landscape of the lung in mild versus severe influenza and to identify key cellular states and pathways associated with disease severity.
Methods: We generated a large-scale single-cell atlas by sequencing over 520,000 cells from the bronchoalveolar lavage fluid of 88 non-immunocompromised adult individuals with mild or severe influenza A and healthy controls. Key findings were validated by flow cytometry and protein quantification, and machine-learning models were used to identify predictive signatures.
Main results: Severe influenza was characterized by profound pulmonary lymphopenia and a massive influx of functionally dysregulated neutrophils. The infiltrating neutrophils were primed for extracellular trap formation, driving a cytokine storm via the S100A8/A9/A12-TLR4 and CXCL8-CXCR1/2 axes. This pathology coincided with the depletion and functional impairment of resident alveolar macrophages and an expansion of pro-inflammatory, monocyte-derived macrophages that amplified neutrophil recruitment. Lymphopenia in severe disease arose from synergistic cell-death programs, while remaining lymphocytes exhibited a dysfunctional state of concurrent exhaustion and hyper-cytotoxicity. Mild influenza featured a coordinated adaptive immune response, distinguished by an enrichment of T follicular helper cells and plasma cells. Machine-earning models identified robust cellular and transcriptional signatures predictive of disease severity.
Conclusions: Our atlas defines the divergent immune trajectories in influenza, revealing specific cellular states and pathways that drive immunopathology and provide novel targets for host-directed therapies.
Keywords: BALF; Influenza; cytokine storm; lymphopenia; scRNA-seq.
. 2026 Mar 16:aamag122.
doi: 10.1093/ajrccm/aamag122. Online ahead of print.
A large-scale single-cell atlas reveals the pulmonary immune panorama in adult patients with influenza
Kun Xiao 1 , Yan Cao 1 , Zhihai Han 1 , Qian Da 2 , Yun Feng 3 , Rong Tian 4 , Laurence Don Wai Luu 5 6 , Li Zhang 7 , Xiaoyan Li 8 , Ruijuan Wang 9 , Qi Li 10 , Mei Hu 11 , Fucheng An 12 , Xiangxin Li 13 , Fei Zhang 14 , Shubin Qiao 15 , Qingrong Nie 16 , Ping Jiang 7 , Xia Ma 17 , Ye Hu 1 , Kaifei Wang 1 , Zhimei Duan 1 , Yang Liu 18 , Jiaxin Wang 1 , Wenjian Xu 19 , Peng Yan 20 , Xiang Gao 21 , Bin Cao 22 , Lixin Xie 1 , Yi Wang 19 23 24
Affiliations
- PMID: 42085240
- DOI: 10.1093/ajrccm/aamag122
Rationale: The host immune determinants that distinguish protective from life-threatening responses to influenza are poorly understood. Identifying drivers of immunopathology in the human lung is critical for developing potential therapies.
Objectives: To define the cellular and molecular immune landscape of the lung in mild versus severe influenza and to identify key cellular states and pathways associated with disease severity.
Methods: We generated a large-scale single-cell atlas by sequencing over 520,000 cells from the bronchoalveolar lavage fluid of 88 non-immunocompromised adult individuals with mild or severe influenza A and healthy controls. Key findings were validated by flow cytometry and protein quantification, and machine-learning models were used to identify predictive signatures.
Main results: Severe influenza was characterized by profound pulmonary lymphopenia and a massive influx of functionally dysregulated neutrophils. The infiltrating neutrophils were primed for extracellular trap formation, driving a cytokine storm via the S100A8/A9/A12-TLR4 and CXCL8-CXCR1/2 axes. This pathology coincided with the depletion and functional impairment of resident alveolar macrophages and an expansion of pro-inflammatory, monocyte-derived macrophages that amplified neutrophil recruitment. Lymphopenia in severe disease arose from synergistic cell-death programs, while remaining lymphocytes exhibited a dysfunctional state of concurrent exhaustion and hyper-cytotoxicity. Mild influenza featured a coordinated adaptive immune response, distinguished by an enrichment of T follicular helper cells and plasma cells. Machine-earning models identified robust cellular and transcriptional signatures predictive of disease severity.
Conclusions: Our atlas defines the divergent immune trajectories in influenza, revealing specific cellular states and pathways that drive immunopathology and provide novel targets for host-directed therapies.
Keywords: BALF; Influenza; cytokine storm; lymphopenia; scRNA-seq.