Single-cell RNA sequencing reveals mucosal BPIFA1-high-expressing neutrophils aid immune defense in SARS-CoV-2 breakthrough infection

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ID: 313453
2026
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Abstract
BACKGROUND: With the viral variants and waning of vaccine-induced immunity over time, SARS-CoV-2 breakthrough infections have become the next challenge following the COVID-19 pandemic, highlighting the need for broader and sustained immune responses. As the first defense against viral invasion, mucosal immunity is inducible by SARS-CoV-2 infection. Previous studies focused on serum antibodies and cellular immunity in the acquired immune, but the specific role of mucosal immunity in breakthrough infection remains to be elucidated. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on nasal swabs and peripheral blood mononuclear cells from a prospective cohort of breakthrough-infected individuals. Findings were validated with flow cytometry and ELISA in a separate multicenter cohort. In vitro experiments using recombinant protein were conducted on the human monocytic leukemia cell THP-1, as effector cells, to investigate underlying mechanisms. RESULTS: Mucosal neutrophils showed the most significant dynamic changes in post-infection. A unique subpopulation of high-BPIFA1-expressing (BPI+) neutrophils was identified and found to be positively correlated with neutralizing antibody and IgG levels in break-through patients (Pt) group.By scRNA-seq, cell communication analysis revealed enhanced interactions between BPI+ neutrophils and macrophages. In vitro, BPIFA1 stimulation activated the NF-κB pathway in THP-1 cells. CONCLUSIONS: BPI+ neutrophils in the respiratory mucosa are pivotal in driving immune responses during breakthrough infection by modulating macrophage activity via the NF-κB pathway. It may trigger the production of interleukin-6, the immunostimulatory phenotype necessary for B cell engagement, to complete the innate-to-adaptive immunity relay, which highlights their potential as a target for novel mucosal vaccine strategies.
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Authors Xue Bai, Shixing Chen, Shengxia Yin, Q H Zhao, Qi Gu, Jinqiu Ran, Junping Shi, Yanliang Zhang, Haibin Ni, Yonglan Pu, Yuehua Chen, Chao Wu, Haiming Xia, Jie Li
Journal The Journal of infectious diseases
Year 2026
DOI
10.1093/infdis/jiag267
URL
https://doi.org/10.1093/infdis/jiag267
Keywords Keywords not found

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