Abstract
Influenza A virus (IAV) infection is a complicated process. After IAVs spread to the lung, extensive pro-inflammatory cytokines and chemokines are released, which largely determine the outcome of infection. Using a single-cell RNA sequencing (scRNA-seq) assay, we systematically and sequentially analyzed the transcriptome of more than 16,000 immune cells in the pulmonary tissue of infected mice, and demonstrated that two waves of pro-inflammatory factors were released. A group of IAV-infected PD-L1+ neutrophils were the major contributor to the first wave at an earlier stage (day 1-3 post infection). Notably, at a later stage (day 7 post infection) when IAV was hardly detected in the immune cells, a group of platelet factor 4-positive (Pf4+)-macrophages generated another wave of pro-inflammatory factors, which were probably the precursors of alveolar macrophages (AMs). Furthermore, single-cell signaling map identified inter-lineage crosstalk between different clusters and helped better understand the signature of PD-L1+ neutrophils and Pf4+-macrophages. Our data characteristically clarified the infiltrated immune cells and their production of pro-inflammatory factors during the immunopathogenesis development, and deciphered the important mechanisms underlying IAV-driven inflammatory reactions in the lung.
Highlights
Aberrant pulmonary immune responses correlate with the pathogenesis of multiple human respiratory viral infections, including Influenza A virus (IAV) infection [1]
The activation of neutrophils was recently reported associated with the most severe and acute infection of IAV in patients [7], and old mice infected with IAV would induced excessive levels of neutrophils and higher levels of cytokines [8], indicating that neutrophils have important roles in the IAV-driven immunopathogenesis Because of the double-edged sword role played by these infiltrated immune cells and the cytokines/chemokines they produced, it is necessary to further explore immune reaction profiles of the lung at different time points during IAV infection
Any cell with less than 200 genes or more than 30% of mitochondrial unique molecular identifier (UMI) counts was filtered out, and only genes with at least one UMI count detected in at least one cell were used for further analysis
Summary
Aberrant pulmonary immune responses correlate with the pathogenesis of multiple human respiratory viral infections, including IAV infection [1]. Immune responses in the lung tissue include both antiviral and inflammatory factors, which play crucial roles in host protection and immunopathogenesis [2, 3]. Studies have highlighted a correlation between IL-6, IL1, and TNF-α levels and the severity of disease symptoms [5, 6, 2] Though these infiltrated cells are required for host protection and recovery, they can exacerbate the immune injury to the lung and worsen clinical symptoms. The activation of neutrophils was recently reported associated with the most severe and acute infection of IAV in patients [7], and old mice infected with IAV would induced excessive levels of neutrophils and higher levels of cytokines [8], indicating that neutrophils have important roles in the IAV-driven immunopathogenesis Because of the double-edged sword role played by these infiltrated immune cells and the cytokines/chemokines they produced, it is necessary to further explore immune reaction profiles of the lung at different time points during IAV infection
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