Document Type

Article

Journal Title

Frontiers in Immunology

Publication Date

2022

Volume

13

Abstract

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes associated with inflammatory diseases. Further evidence from conditional knockout mouse models reveals that IFN-γ receptor signaling in myeloid cells, particularly CD11c+ mononuclear phagocytes, directly promotes TNF-α hyperproduction and inflammatory lung damage. Collectively, the findings from this study, ranging from cell-intrinsic gene expression to overall disease outcome, demonstrate that influenza-induced IFN-γ triggers myeloid cell hyperresponsiveness to MRSA, thereby leading to excessive inflammatory response and lethal lung damage during coinfection.

MeSH Headings

Animals, Anti-Bacterial Agents, Coinfection, Humans, Influenza, Human, Interferon-gamma, Lung Injury, Methicillin-Resistant Staphylococcus aureus, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Respiratory Distress Syndrome, Transcriptome, Tumor Necrosis Factor-alpha

ISSN

1664-3224

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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