tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Yan Cao[SUP] 1 [/SUP], Zhihai Han[SUP] 1 [/SUP], Qian Da[SUP] 2 [/SUP], Yun Feng[SUP] 3 [/SUP], Rong Tian[SUP] 4 [/SUP], Laurence Don Wai Luu[SUP] 5 6 [/SUP], Li Zhang[SUP] 7 [/SUP], Xiaoyan Li[SUP] 8 [/SUP], Ruijuan Wang[SUP] 9 [/SUP], Qi Li[SUP] 10 [/SUP], Mei Hu[SUP] 11 [/SUP], Fucheng An[SUP] 12 [/SUP], Xiangxin Li[SUP] 13 [/SUP], Fei Zhang[SUP] 14 [/SUP], Shubin Qiao[SUP] 15 [/SUP], Qingrong Nie[SUP] 16 [/SUP], Ping Jiang[SUP] 7 [/SUP], Xia Ma[SUP] 17 [/SUP], Ye Hu[SUP] 1 [/SUP], Kaifei Wang[SUP] 1 [/SUP], Zhimei Duan[SUP] 1 [/SUP], Yang Liu[SUP] 18 [/SUP], Jiaxin Wang[SUP] 1 [/SUP], Wenjian Xu[SUP] 19 [/SUP], Peng Yan[SUP] 20 [/SUP], Xiang Gao[SUP] 21 [/SUP], Bin Cao[SUP] 22 [/SUP], Lixin Xie[SUP] 1 [/SUP], Yi Wang[SUP] 19 23 24 [/SUP]
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[SUP] 1 [/SUP], Yan Cao[SUP] 1 [/SUP], Zhihai Han[SUP] 1 [/SUP], Qian Da[SUP] 2 [/SUP], Yun Feng[SUP] 3 [/SUP], Rong Tian[SUP] 4 [/SUP], Laurence Don Wai Luu[SUP] 5 6 [/SUP], Li Zhang[SUP] 7 [/SUP], Xiaoyan Li[SUP] 8 [/SUP], Ruijuan Wang[SUP] 9 [/SUP], Qi Li[SUP] 10 [/SUP], Mei Hu[SUP] 11 [/SUP], Fucheng An[SUP] 12 [/SUP], Xiangxin Li[SUP] 13 [/SUP], Fei Zhang[SUP] 14 [/SUP], Shubin Qiao[SUP] 15 [/SUP], Qingrong Nie[SUP] 16 [/SUP], Ping Jiang[SUP] 7 [/SUP], Xia Ma[SUP] 17 [/SUP], Ye Hu[SUP] 1 [/SUP], Kaifei Wang[SUP] 1 [/SUP], Zhimei Duan[SUP] 1 [/SUP], Yang Liu[SUP] 18 [/SUP], Jiaxin Wang[SUP] 1 [/SUP], Wenjian Xu[SUP] 19 [/SUP], Peng Yan[SUP] 20 [/SUP], Xiang Gao[SUP] 21 [/SUP], Bin Cao[SUP] 22 [/SUP], Lixin Xie[SUP] 1 [/SUP], Yi Wang[SUP] 19 23 24 [/SUP]
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.